Estrogen receptor-modulating compounds

ABSTRACT

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application 62/620,441 filed on Jan. 22, 2018. Thedisclosure of this prior application is considered part of thedisclosure of this application and is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, methods of making suchcompounds, pharmaceutical compositions comprising such compounds, andmethods of using such compounds to treat, prevent or diagnose diseasesor conditions that are estrogen sensitive, estrogen receptor dependentor estrogen receptor mediated.

BACKGROUND OF THE INVENTION

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 17β-estradiol and estrone. The estrogen receptor hasbeen found to have two isoforms, ER-α (ESR1) and ER-β (ESR2). Estrogensand estrogen receptors are implicated in a number of diseases orconditions, such as breast cancer, lung cancer, ovarian cancer, coloncancer, prostate cancer, endometrial cancer, uterine cancer, as well asothers diseases or conditions, such as infertility, osteoporosis,vaginal atrophy, dyspareunia, contraception, male hypogonadism,gynecomastia, breast pain, and accordingly find use in the treatment ofthese and other conditions and diseases that are at least in partattributable to regulation of the estrogen receptor.

Selective estrogen receptor modulators (SERMs) are a class of drugs thatact on the estrogen receptor. They tend to be competitive ligands of theestrogen receptor. A characteristic that distinguishes these substancesfrom pure ER agonists and antagonists (that is, full agonists and silentantagonists) is that their action is different in various tissues,thereby granting the possibility to selectively inhibit or stimulateestrogen-like action in various tissues. For example, ER-α is typicallyfound as the predominant form in the female reproductive tract andmammary glands, while ER-β is found in higher levels in vascularendothelial cells, bone, and male prostate tissue. Different tissueshave different degrees of sensitivity to and activity of endogenousestrogens, so SERMs produce estrogenic or antiestrogenic effectsdepending on the specific tissue in question as well as the percentageof intrinsic activity (IA) of the SERM. Moreover, their levels invarious tissues may change in response to physical development, aging ordisease state. Antagonizing at the ER can either occur throughcompetitive inhibition, wherein one ligand displaces a more agonisticligand (eg 17β-estradiol) and signals to a lesser degree or not at allrelative to the agonist ligand. There is a second mode of inhibitingER-agonist signaling and this comprises the binding of a ligand to ERand inducing a conformation or conformations that trigger thedegradation of the ER in the proteasome. Often, the degradation istriggered by ubiquination and/or palmoylation of ER subsequent to abinding event of the degradation-triggering compound. Compounds thatbind ER and accelerate its degradation are often referred to asselective estrogen receptor degraders (“SERDs”). Referring to a compoundas a SERM or SERD is a general way to focus on that aspect of itspharmacology. As it turns out, many compounds that function as SERMs,meaning they have at least some agonist activity in some (but not all)ER-expressing tissues, can also trigger at least some receptordegradation. Accordingly, it should be appreciated that many if not mostof the compounds falling under the embodiments of this inventionrepresent a spectrum of SERM/SERD activity. Whether SERMs, SERDs andSERM/SERDs, the compounds of the present disclosure are able to achievethe methods disclosed herein.

SUMMARY OF THE INVENTION

In one aspect, presented herein are compounds of Formulas I to VII, I′to X′, or a pharmaceutically acceptable salt, solvate or prodrugthereof, that modify the effects of endogeneous estrogens acting throughER and/or trigger ER degradation, and therefore, are useful as agentsfor the treatment or prevention of diseases or conditions in which theactions of estrogens and/or estrogen receptors are involved in theetiology or pathology of the disease or condition or contribute to atleast one symptom of the disease or condition and wherein such actionsof estrogens and/or estrogen receptors are undesirable. In someembodiments, compounds disclosed herein are selective estrogen receptordegrader compounds.

In one aspect, compounds of Formulas I to VII, I′ to X′, or apharmaceutically acceptable salt, solvate or prodrug thereof, are usefulfor the treatment of ER-related diseases or conditions including, butnot limited to, ER-α dysfunction associated with cancer such as, breastcancer, lung cancer, colorectal cancer, endometrial cancer, prostatecancer, ovarian and uterine cancer, including metastatic cancers.

In one aspect, described herein are compounds of Formulas I to VII, I′to X′, and pharmaceutically acceptable salts, solvates, metabolites andprodrugs thereof. Compounds described herein are estrogen receptormodulators. In some embodiments, the compound of Formulas I to VII or I′to X′ is an estrogen receptor antagonist. In some embodiments, thecompound of Formulas I to VII or I′ to X′ displays minimal estrogenreceptor agonist activity. In some embodiments, in the context oftreating cancers, the compound of Formulas I to VII or I′ to X′ mayoffer improved therapeutic activity characterized by complete orlonger-lasting tumor regression, a lower incidence or rate ofdevelopment of resistance to treatment, and/or a reduction in tumorinvasiveness.

In some embodiments, compounds disclosed herein have high specificityfor the estrogen receptor and have desirable, tissue-selectivepharmacological activities. Desirable, tissue-selective pharmacologicalactivities include, but are not limited to, ER antagonist activity inbreast cells and no ER agonist activity in uterine cells. In someembodiments, compounds disclosed herein are estrogen receptor degradersthat display full estrogen receptor antagonist activity with negligibleor minimal estrogen receptor agonist activity.

In some embodiments, compounds disclosed herein are estrogen receptordegraders. In some embodiments, compounds disclosed herein are estrogenreceptor antagonists. In some embodiments, compounds disclosed hereinhave minimal or negligible estrogen receptor agonist activity.

In some embodiments, presented herein are compounds selected from thegroup consisting of active metabolites, tautomers, pharmaceuticallyacceptable solvates, pharmaceutically acceptable salts, and prodrugs ofa compound of Formulas I to VII or I′ to X′.

In certain embodiments, the present invention describes a compound ofFormula I:

wherein:

B is nitrogen or carbon;

D is carbon;

A is a fused ring system selected from the group consisting of:

each R_(e) is independently selected from the group consisting ofhydrogen, halogen, OH, O(CO)R, O(CO)NR₁R₂, OPO₃, SO₃, O(SO₂)NR₁R₂, orwherein two adjacent R_(e) together form:

each R is independently C₁-C₆ alkyl or aryl;

each R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is hydrogen, C₁-C₁₂ acyl, or C₁-C₁₂ acyloxy;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(h) is independently hydrogen or CH₃;

R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine,chlorine or bromine;

each R_(a) is independently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, bromine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃,O(SO₂)NR₁R₂, or two adjacent R_(a) together form:

X is O, S, CH₂, NH or a bond when B is carbon, or CH₂ or a bond when Bis nitrogen;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N;

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl;

or a pharmaceutically acceptable salt thereof.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In certain embodiments, provided herein are pharmaceutical compositionscomprising a compound selected from the group consisting of formulasI-VII, I′ to X′, and all structural embodiments described herein and atleast one pharmaceutically acceptable excipient.

In certain embodiments, provided herein is a method of modulating anestrogen receptor in a cell, comprising the administration of a compoundto said cell wherein said compound is selected from the group consistingof formulas I-VII, I′ to X′, and all the structural embodimentsdescribed herein, or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided herein is a method of identifying acompound capable of modulating an estrogen receptor comprisingcontacting a cell expressing an estrogen receptor with a compoundaccording to formula I, and monitoring the effect of the compound on thecell.

Also described herein is a prodrug of a compound selected from the groupconsisting of formulas I-VII, I′ to X′, and all structural embodimentsdescribed herein. Also described herein is a pharmaceutically acceptablesalt of a prodrug of a compound selected from the group consisting offormulas I-VII, I′ to X′, and all structural embodiments describedherein. In some embodiments, the pharmaceutically acceptable salt of theprodrug of a compound of Formulas I-VII, I′ to X′, is a hydrochloridesalt.

In some embodiments, described herein is a pharmaceutical compositioncomprising a compound selected from the group consisting of formulasI-VII, I′ to X′, and all structural embodiments described herein or apharmaceutically acceptable salt or prodrug of a compound selected fromthe group consisting of formulas I-VII, I′ to X′, and all structuralembodiments described herein. In some embodiments, the pharmaceuticalcomposition is formulated for intravenous injection, subcutaneousinjection, oral administration, or topical administration. In someembodiments, the pharmaceutical composition is a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion.

This invention also provides a method of treating (e.g., preventing, orameliorating the symptoms associated with, or reducing the incidence of,reducing the pathogenesis of, facilitating the recovery from or delayingthe onset of) a disease, syndrome, illness, or symptom associated withinsufficient or overabundant estrogen levels in a mammal in needthereof, wherein said method comprises the administration to said mammalof an effective amount of a compound selected from the group consistingof formulas I-VII, I′ to X′, and all structural embodiments describedherein or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of formulas I-VII, I′to X′, or one of the structural embodiments described herein, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient. In a particular embodiment, the mammal is a human.

In certain aspects, this invention describes a method of treating (e.g.,preventing, or ameliorating the symptoms associated with, or reducingthe incidence of, reducing the pathogenesis of, facilitating therecovery from or delaying the onset of) prostate cancer, breast cancer,endometrial cancer, lung cancer, hepatocellular cancer, lymphoma,multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroidcancer, testicular cancer, leukemia, and ovarian cancer in a mammal inneed thereof comprising the administration to said mammal of a compoundselected from the group consisting of formulas I-VII, I′ to X′, and allstructural embodiments described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising acompound selected from the group consisting of formulas I-VII, I′ to X′,and all structural embodiments described herein includingpharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable excipient. In an embodiment, the mammal is a human. In someembodiments, the cancer is positive for the expression of ESR1. Incertain embodiments, the cancers are resistant to prior lines oftreatment (e.g., prior endocrinological therapy). In certainembodiments, the cancer progresses after exposure to one or more agentsselected from the group consisting of tamoxifen, toremifene, letrozole,aromasin, anastrazole, and faslodex. In some embodiments, the treatmentis in adjuvant setting and in some embodiments the treatment is in themetastatic setting. In certain embodiments, SERD and/or SERMS compoundsdisclosed herein are combined with other active compounds including,cdk4/6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, and Her2inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

“Selective estrogen receptor modulator” or “SERM” as used herein, refersto a molecule that differentially modulates the activity of estrogenreceptors in different tissues. For example, in some embodiments, a SERMdisplays ER antagonist activity in some tissues and ER agonist activityin other tissues. In some embodiments, a SERM displays ER antagonistactivity in some tissues and minimal or no ER agonist activity in othertissues. In some embodiments, a SERM displays ER antagonist activity inbreast tissues, ovarian tissues, endometrial tissues, and/or cervicaltissues.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonism” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “degrader” as used herein, refers to a small molecule agentthat binds to a nuclear hormone receptor and subsequently lowers thesteady state protein levels of said receptor. In some embodiments, adegrader as described herein lowers steady state estrogen receptorlevels by at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In someembodiments, a degrader as described herein lowers steady state estrogenreceptor levels by at least 65%. In some embodiments, a degrader asdescribed herein lowers steady state estrogen receptor levels by atleast 85%.

The term “selective estrogen receptor degrader” or “SERD” as usedherein, refers to a small molecule agent that preferentially binds toestrogen receptors versus other receptors and subsequently lowers thesteady state estrogen receptor levels. In addition, SERD can mean acompound that degrades in one cell or tissue type more than in another,thus expressing possibly SERM type activity while effecting degradationdifferentially depending on the cellular or tissue context.

The term “Estrogen Receptor-dependent”, as used herein, refers todiseases or conditions that would not occur, or would not occur to thesame extent, in the absence of estrogen receptors.

The term “Estrogen Receptor-mediated”, as used herein, refers todiseases or conditions that are at least in part dependent on estrogensignaling for their status.

The term “Estrogen Receptor-sensitive”, as used herein, refers todiseases or conditions that would not occur, or would not occur to thesame extent, in the absence of estrogens. Estrogen receptor sensitivealso refers to cells or tissues that respond to the presence of estrogenreceptor agonists, antagonists, SERMs and/or SERDs.

The term “cancer” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma),ovary, pancreas or other endocrine organ (thyroid), prostate, or skin(melanoma or basal cell cancer)) or hematological tumors (such as theleukemias and lymphomas) at any stage of the disease with or withoutmetastases.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I through VII, I′ to X′, or apharmaceutically acceptable salt thereof, and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I through VII, I′ to X′, or apharmaceutically acceptable salt thereof, and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In some embodiments, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

In the context of this disclosure, the phrase “formula I through VII,”“formula I to VII” or “formula I-VII” is meant to, in each instance,include compounds of formula I, II, IIa, IIb, IIc, IId, IIe, IIf, IIg,IIh, IIj, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IV, IVa, IVb, IVc,IVd, IVe, IVf, IVg, IVh, IVj, V, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, VI,VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VII.

The term “alkyl” as used herein refers to both straight and branch chainhydrocarbon radicals, having the number of carbon atoms falling withinthe specified range. For example, C₁₋₄ alkyl means that a hydrocarbonradical is attached that may contain anywhere from 1 to 4 carbon atomswith the remaining valence filled in by hydrogen atoms. The definitionalso includes separately each permutation as though it were separatelylisted. Thus, C₁₋₂ alkyl includes methyl and ethyl. The term C₁₋₃ alkylincludes methyl, ethyl, propyl and 2-propyl. The term C₁₋₄ alkylincludes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyland tert-butyl. The term C₁₋₅ alkyl includes methyl, ethyl, 2-propyl,n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl,and tert-pentyl, iso-pentyl.

The term “halogen” as used herein refers to a fluorine, chlorine,bromine or iodine radical.

The term “haloalkyl” refers to an alkyl radical wherein said alkylradical is the same as defined for the term “alkyl” except that thealkyl radical additionally has from 1 to 5 halogen atoms attached to thealkyl chain. For example, C₁ haloalkyl includes —CH₂F, —CHF₂, —CF₃ andthe like, C₁₋₂ haloalkyl includes —CH₂F, CHF₂, CF₃, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃, —CF₂CHF₂, —CF₂CF₃ and the like. C₁₋₃ haloalkyl is defined toinclude —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CF₂CF₃, —CHClCH₃,—CH₂CH₂C₁, —CH₂CH₂CH₂F, —CH₂CH₂CF₃, and the like. C₁₋₄ haloalkyl isdefined to include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃, —CF₂CF₃,—CHClCH₃, —CH₂CH₂C₁, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, CHClCF₂CH₂CH₃,CF₂CH₂CH₂CHF₂, CH₂CH₂CH₂CH₂F, CH₂CH₂CH₂CH₂C₁, and the like. The term“fluoroalkyl” as in “C₁-C₄fluoroalkyl” includes C₁, C₂, C₃ and C₄ alkylchains, straight or branched, with from 1-4 fluorine atoms such as—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CF₂CHF₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃,—CHFCF₃, —CF₂CF₃, —CH₂CH₂CF₃, CH₂CH₂CH₂F, —CH₂CH₂CH₂CF₃, CF₂CH₂CH₂CHF₂,CH₂CH₂CH₂CH₂F, CH(CH₃)CH₂F, CH₂(CH)(CH₃)CH₂F, CH₂(CH)(CH₂F)(CH₂F).

The term “aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

The term “acyl” refers to a group having the general formula —(CO)-alkylwherein said alkyl radical is the same as defined for the term “alkyl”and wherein the alkyl portion of the acyl group has the number of carbonatoms falling within the specified range.

The term “acyloxy” refers to a group having the general formula—O(CO)-alkyl wherein said alkyl radical is the same as defined for theterm “alkyl” and wherein the alkyl portion of the acyloxy group has thenumber of carbon atoms falling within the specified range.

The compounds of this invention may contain at least one stereocenterand therefore, exist in various stereoisomeric forms. Stereoisomers arecompounds which differ only in their spatial arrangement. Enantiomersare pairs of stereoisomers whose mirror images are not superimposable,most commonly because they contain an asymmetrically substituted carbonatom that acts as a chiral center. “Enantiomer” means one of a pair ofmolecules that are mirror images of each other and are notsuperimposable. Diastereomers are stereoisomers that are not related asmirror images, most commonly because they contain two or moreasymmetrically substituted carbon atoms. “R” and “S” represent theconfiguration of substituents around one or more chiral carbon atoms.Thus, “R” and “S” denote the relative configurations of substituentsaround one or more chiral carbon atoms. When the stereochemistry of adisclosed compound is named or depicted by structure, the named ordepicted stereoisomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%or 99.9% by weight pure relative to the other stereoisomers. When asingle enantiomer is named or depicted by structure, the depicted ornamed enantiomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or99.9% by weight optically pure. Percent optical purity by weight is theratio of the weight of the enantiomer over the weight of the enantiomerplus the weight of its optical isomer.

The compounds of the invention may be prepared as individual isomers byincorporating or starting with a specific isomer, isomer-specificsynthesis, separation of diastereomers or resolution from an isomericmixture. Conventional resolution techniques include forming the salt ofa free base of each isomer of an isomeric pair using an optically activeacid (followed by fractional crystallization and regeneration of thefree base), forming the salt of the acid form of each isomer of anisomeric pair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

Reference to a use of a compound of Formula I through VII or I′ to X′ ora composition that includes a compound of Formula I through VII or I′ toX′, wherein the compound contains at least one stereomeric center,refers to the racemate or in any optical purity of the compound ofFormula I through VII or I′ to X′ in the composition, including but notlimited to an optically pure compound.

In some embodiments, the enantiomeric ratio of the compound of Formula Ithrough VII or I′ to X′ having a stereomeric center is greater than90:10. In some embodiments, the enantiomeric ratio of the compound ofFormula I through VII or I′ to X′ is greater than 95:5. In someembodiments, the enantiomeric ratio of the compound of Formula I throughVII or I′ to X′ is greater than 99:1. In some embodiments, the compoundof Formula I through VII or I′ to X′ is optically pure.

Where compounds of Formula I through VII or I′ to X′ include one or morebasic sites such as amines, acid addition salts can be made and thisinvention includes such acid addition salts. Some representative(non-limiting) acid addition salts include hydrochloride, hydrobromide,hydroiodide, acetate, benzenesulfonate, mesylate, besylate, benzoate,tosylate, citrate, tartrate, sulfate, bisulfate, lactate, maleate,mandelate, valerate, laurate, caprylate, propionate, succinate,phosphate, salicylate, napsylate, nitrate, tannate, resorcinate and thelike, including multiprotic salts as well as mixtures of the acidaddition salts. In cases where an amine is present, this invention alsoembraces quaternized ammonium salts of those amines. Likewise, wherecompounds of this invention include one or more acid sites such ascarboxylic acids, phenols and the like, basic addition salts can be madeand this invention includes such basic addition salts. For example, somerepresentative (non-limiting) acidic compounds of this invention may bepresent as their lithium, sodium, potassium, ammonium, trialkyammonium,calcium, magnesium, barium and the like.

The compounds of this invention can also be present as solvates and suchsolvates are embraced within the scope of this invention even where notexplicitly described. Such solvates are preferably hydrates but can besolvates comprised of other solvents, preferably where those solventsare considered to be non-toxic or at least acceptable for administrationto mammals, preferably humans. The solvates can be stoichiometric ornon-stoichiometric, singular or in combination. Some exemplary solvatesinclude water, ethanol, acetic acid and the like.

The compounds of this invention, when used as therapeutics can beadministered by any method known to one of skill in the art such asorally, bucally, intravenously, subcutaneously, intramuscularly,transdermally, intradermally, intravascularly, intranasally,sublingually, intracranially, rectally, intratumorally, intravaginally,intraperitonealy, pulmonary, ocularly and intratumorally.

When administered, the compounds and compositions of this inventionmaybe given once daily or with multiple daily doses such as twice perday, three times per day and four times per day.

In one embodiment of this invention, the compound is administered orallywhere it can be formulated for solid dosage administration or liquiddosage administration. Solid dosage administration can be in the form ofa tablet, granule, capsule, pill, pellet, powder and the like. Liquiddosage formulations include syrups, solutions, gels, suspensions,elixirs, emulsions, colloids, oils, and the like.

As mentioned previously, the compounds of this invention may be solidsand when present as solids, they maybe of defined particle size. Wherethe compound of this invention is not particularly water soluble, it issometimes preferable to administer the compound with a certain particlesize—a particle size with a preferred range where the average meanparticle size diameter is under 100 microns, or 75 microns, or 50microns, or 35 microns, or 10 microns or 5 microns.

Solid dosage formulations will comprise at least one compound of thisinvention together with one or more pharmaceutical excipients.

The solid dosage forms of this invention also include capsules whereinthe drug is enclosed inside the capsule either as a powder together withoptional excipients or as granules containing usually including one ormore excipients together with the drug and wherein the granule in turncan be optionally coated, for example, enterically or non-enterically.

The compounds of this invention may be employed alone or in combinationwith other therapeutic agents. By way of non-limiting example, thecompounds of this invention can be used in combination with one or moreof a cdk4/6 inhibitor, PI3K inhibitor, mTOR inhibitor, and a taxane.

The compounds of this invention may be administered according todifferent dosage scheduling and the dosage may be adjusted as deemednecessary by the subject or preferably by the subject in consultationwith a qualified practitioner of medicine. Dosing of the compounds ofthis invention can take place by multiple routes and consequently, thedosing schedule and amounts are dependent not only on the particularsubject's weight, sex, age, therapy contemplated, etc but also by theroute of the drug chosen.

By way of non-limiting example, the compounds of this invention may beconsidered for dosing by the oral route with optimal efficacy and/orsafety being the goal.

It is understood that the amount of compound dosed per day can beadministered every day, every other day, every 2 days, every 3 days,every 4 days, every 5 days, etc. For example, with every other dayadministration, a 5 mg per day dose can be initiated on Monday with afirst subsequent 5 mg per day dose administered on Wednesday, a secondsubsequent 5 mg per day dose administered on Friday, etc. In oneembodiment, a compound is dosed once every seven days.

This invention also provides a method of treating (e.g., preventing, orameliorating the symptoms associated with, or reducing the incidence of,reducing the pathogenesis of, facilitating the recovery from or delayingthe onset of) a disease, syndrome, illness, or symptom associated withinsufficient or overabundant estrogen levels in a mammal in needthereof, wherein said method comprises the administration to said mammalof an effective amount of a compound selected from the group consistingof formulas I-VII, I′ to X′, and all structural embodiments describedherein or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of formulas I-VII, I′to X′, or one of the structural embodiments described herein, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient. In a particular embodiment, the mammal is a human.

In certain aspects, this invention describes a method of treating (e.g.,preventing, or ameliorating the symptoms associated with, or reducingthe incidence of, reducing the pathogenesis of, facilitating therecovery from or delaying the onset of) prostate cancer, breast cancer,endometrial cancer, lung cancer, hepatocellular cancer, lymphoma,multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroidcancer, testicular cancer, leukemia, and ovarian cancer in a mammal inneed thereof comprising the administration to said mammal of a compoundselected from the group consisting of formulas I-VII, I′ to X′, and allstructural embodiments described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising acompound selected from the group consisting of formulas I-VII, I′ to X′,and all structural embodiments described herein includingpharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable excipient. In an embodiment, the mammal is a human. In someembodiments, the cancer is positive for the expression of ESR1. Incertain embodiments, the cancers are resistant to prior lines oftreatment (e.g., prior endocrinological therapy). In certainembodiments, the cancer progresses after exposure to one or more agentsselected from the group consisting of tamoxifen, toremifene, letrozole,aromasin, anastrazole, and faslodex. In some embodiments, the treatmentis in adjuvant setting and in some embodiments the treatment is in themetastatic setting. In certain embodiments, SERD and/or SERMS compoundsdisclosed herein are combined with other active compounds including,cdk4/6 inhibitors, PI3k inhibitors, mTOR inhibitors, taxanes, and Her2inhibitors.

Also provided herein is a method of inhibiting tumor growth or producingtumor regression in a subject having an estrogen receptor alpha-positivecancer comprising administering to said subject a therapeuticallyeffective amount of a compound of Formulas I to VII or I′ to X′ or apharmaceutically acceptable salt, solvate or prodrug thereof. In someembodiments, the estrogen receptor alpha-positive cancer is adrug-resistant estrogen receptor alpha-positive cancer. In someembodiments, the cancer is selected from breast cancer, uterine cancer,ovarian cancer, and pituitary cancer. In some embodiments, the cancer isbreast cancer. In some embodiments, the cancer is metastatic. In someembodiments, the cancer is positive for the mutant estrogen receptoralpha comprising one or more mutations selected from the groupconsisting of Y537X₁ (wherein X₁ is S, N, or C), L536X₂ (wherein X₂ is Ror Q), P535H, V534E, S463P, V392I, E380Q, D538G, and combinationsthereof. In some embodiments, the mutation is Y537S. In someembodiments, the subject has osteoporosis or a high risk ofosteoporosis. In some embodiments, the subject is a pre-menopausalwoman. In some embodiments, the subject is a post-menopausal woman whohad relapsed or progressed after previous treatment with SERMs, CDKinhibitors, and/or AIs. In some embodiments, the tumor is resistant to adrug selected from the group consisting of anti-estrogens (e.g.,tamoxifen or fulvestrant), aromatase inhibitors (e.g., aromasin), CDKinhibitors (e.g., abemaciclib, ribociclib, or palbociclib), andcombinations thereof. In some embodiments, the therapeutically effectiveamount of a compound of Formulas I to VII or I′ to X′ or apharmaceutically acceptable salt, solvate or prodrug thereof is employedin combination with one or more of an anti-estrogen, an aromataseinhibitor, a CDK inhibitor, a PI3K inhibitor, an mTOR inhibitor, and ataxane.

Also provided herein is a method of inhibiting tumor growth or producingtumor regression in a subject having a mutant estrogen receptor alphapositive-cancer comprising administering to said subject atherapeutically effective amount of a compound of Formulas I to VII orI′ to X′ or a pharmaceutically acceptable salt, solvate or prodrugthereof. In some embodiments, the cancer is selected from breast cancer,uterine cancer, ovarian cancer, and pituitary cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is metastatic. In some embodiments, the cancer is positive forthe mutant estrogen receptor alpha comprising one or more mutationsselected from the group consisting of Y537X₁ (wherein X₁ is S, N, or C),L536X₂ (wherein X₂ is R or Q), P535H, V534E, S463P, V392I, E380Q, D538G,and combinations thereof. In some embodiments, the mutation is Y537S. Insome embodiments, the subject has osteoporosis or a high risk ofosteoporosis. In some embodiments, the subject is a pre-menopausalwoman. In some embodiments, the subject is a post-menopausal woman whohad relapsed or progressed after previous treatment with SERMs, CDKinhibitors, and/or AIs. In some embodiments, the tumor is resistant to adrug selected from the group consisting of anti-estrogens (e.g.,tamoxifen or fulvestrant), aromatase inhibitors (e.g., aromasin), CDKinhibitors (e.g., abemaciclib, ribociclib, or palbociclib), andcombinations thereof. In some embodiments, the therapeutically effectiveamount of a compound of Formulas I to VII or I′ to X′ or apharmaceutically acceptable salt, solvate or prodrug thereof is employedin combination with one or more of an anti-estrogen, an aromataseinhibitor, a CDK inhibitor, a PI3K inhibitor, an mTOR inhibitor, and ataxane.

Also provided herein is a method of treating breast cancer in a subjecthaving a drug-resistant estrogen receptor alpha-positive cancercomprising administering to said subject a therapeutically effectiveamount of a compound of Formulas I to VII or I′ to X′ or apharmaceutically acceptable salt, solvate or prodrug thereof. In someembodiments, the drug resistant breast cancer is resistant to one ormore antiestrogens (e.g., tamoxifen, toremifene, fulvestrant), CDKinhibitors (e.g., abemaciclib, ribociclib, or palbociclib), and/oraromatase inhibitors (e.g., aromasin, letrozole, anastrozole). In someembodiments, the therapeutically effective amount of a compound ofFormulas I to VII or I′ to X′ or a pharmaceutically acceptable salt,solvate or prodrug thereof is employed in combination with one or moreof an anti-estrogen, an aromatase inhibitor, a CDK inhibitor, a PI3Kinhibitor, an mTOR inhibitor, and a taxane. In some embodiments, thesubject expresses at least one mutant estrogen receptor alpha selectedfrom D538G, Y537S, Y537N, Y537C, E380Q, S463P, L536R, L536Q, P535H,V392I and V534E. In some embodiments, the mutant estrogen receptor alphais selected from Y537S, Y537N, Y537C, D538G, L536R, S463P and E380Q. Insome embodiments, the mutant receptor alpha is Y537S. In someembodiments, the subject is a post-menopausal woman. In someembodiments, the subject is first identified for treatment throughmeasuring for increased expression of one or more genes selected fromABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1,BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1,CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2,DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4,FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2,KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2K4, MCL1, MDM2, MDM4,MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM,NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR,ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2,and VHL. In some embodiments, the one or more genes are selected fromAKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1 and MTOR.

The compounds of this invention can be prepared by a variety ofsynthetic routes and techniques known to those of skill in the art. Theprocesses disclosed herein should not be construed as limiting theexamples or scope of the invention in any way but rather are provided asjust some of the representative ways that the compounds of thisinvention can be or were prepared.

In some cases, protective groups are employed in the synthesis of thecompounds of this invention and it should be appreciated that there area diverse array of protective groups and strategies that can be employedin organic synthesis (T. W. Green and P. G. M. Wuts (2006) Greene'sProtective Groups in Organic Synthesis, herein incorporated by referencein its entirety) and that where a protective group is referred togenerically, any appropriate protective group should be considered.

In some instances, leaving groups are employed in the synthesis ofcompounds of this invention. Where a specific leaving group is referredto, it should be appreciated that other leaving groups might also beused. Leaving groups typically include those groups that can stabilizean anion. In the case of nucleophilic aromatic substitutions, theleaving group may be an anion or a neutrally charged group. In somecases, the leaving group for nucleophilic aromatic substitution may be agroup that is not typically considered to be a stabilized anion (e.g.fluoride or hydride). While not intending to be bound by theory or theexamples, some typical nucleophilic leaving groups include halogens,sulfonates (0-mesylates, 0-tosylates, etc.), hydrides, quaternizedamines, nitro, and the like. Additional discussion and examples can befound in leading textbooks on organic chemistry including, for example,March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5^(th) Edition, which is herein incorporated by reference inits entirety.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

Accordingly, in one embodiment, the present invention provides novelpharmaceutically active compounds or pharmaceutical salts thereof offormula I.

wherein:

B is nitrogen or carbon;

D is carbon;

A is a fused ring system selected from the group consisting of:

each R_(e) is independently hydrogen, halogen, OH, O(CO)R, O(CO)NR₁R₂,OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is hydrogen, C₁-C₁₂ acyl; C₁-C₁₂ acyloxy;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(h) is independently hydrogen or CH₃;

R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine,chlorine or bromine;

each R_(a) is independently selected from: H, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, phenyl (optionally substituted with 1-3 groups that arefluorine, chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl,CN, fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, ortwo adjacent Ra together form:

X is O, S, CH₂, NH or a bond when B is carbon, or CH₂ or a bond when Bis nitrogen;

Y and Z are each independently CR_(f) or N;

U and V are each independently CR_(a) or N;

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R is independently H or C₁-C₃alkyl;or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In some embodiments, the compound of formula I is the compound. In otherembodiments, it is a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a pharmaceuticallyacceptable salt, solvate or prodrug thereof.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt.

In other embodiments, the compound of formula I is a prodrug. In yetother embodiments, the compound of formula I is the pharmaceuticallyacceptable salt of the prodrug. In some aspects the pharmaceuticallyacceptable salt of the prodrug of a compound of Formula I is ahydrochloride salt.

In some embodiments, a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula I is described. In other embodiments, the pharmaceuticalcomposition is formulated for intravenous injection, subcutaneousinjection, oral administration, or topical administration. In certainembodiments, the pharmaceutical composition is a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion.

In some embodiments of formula I compounds, W is—CH₂—CH₂—NH—CH₂—CH₂—CH₃; in other embodiments W is—CH₂—CH₂—NH—CH₂—CH₂—CH₂F.

In certain embodiments of formula I compounds, B is carbon. When B iscarbon, X is O, S, CH₂, NH or a bond. In some embodiments when B iscarbon, X is O, CH₂, or a bond. In other embodiments, B is nitrogen.When B is nitrogen X is CH₂ or a bond. In certain embodiments, when B isnitrogen, X is CH₂.

In some embodiments of formula I compounds, A is selected from the groupconsisting of:

In other embodiments of formula I compounds, A is:

In certain embodiments of formula I compounds, B and D are adjacent ringatoms on the A ring.

In some other embodiments of formula I compounds, each R_(e) isindependently hydrogen, halogen, OH, O(CO)R, O(CO)NR₁R₂, OPO₃, and OSO₃,O(SO₂)NR₁R₂, or wherein two adjacent R_(e) together form:

In certain embodiments of formula I compounds, each R_(e) isindependently selected from the group consisting of hydrogen, halogen,OH, O(CO)R, O(CO)NR₁R₂, OPO₃, and OSO₃, O(SO₂)NR₁R₂. In otherembodiments of formula I compounds, each R_(e) is independently hydrogenor OH.

In certain other embodiments of formula I compounds, two adjacent R_(a)together form:

In embodiments of formula I compounds where two adjacent R_(a) togetherform:

any other R_(a) are each independently hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, and O(SO₂)NR₁R₂. In other embodiments of formulaI compounds, at least one R_(a) is H, or at least two R_(a) are H.

In some embodiments of formula I compounds, each R_(h) is independentlyhydrogen or CH₃. In certain embodiments of formula I compounds, at leastone Rh is hydrogen; in other embodiments of formula I compounds, bothare hydrogen.

In still other embodiments of formula I compounds, R is C₁-C₆ alkyl; inothers, R is aryl.

In certain embodiments of formula I compounds, R₁ and R₂ are eachindependently hydrogen or C₁-C₆ alkyl. In some embodiments of formula Icompounds, at least one of R₁ and R₂ is hydrogen.

In other embodiments of formula I compounds, each R₃ is hydrogen, C₁-C₁₂acyl; or C₁-C₁₂ acyloxy.

In other embodiments of formula I compounds, each R₄ is independentlyhydrogen, C₁-C₃alkyl, fluorine or chlorine. When R₄ is C₁-C₃ alkyl, itis methyl, ethyl, or C₃ alkyl, or any combination or subcombinationthereof. In some embodiments of formula I compounds, R₄ is hydrogen. Insome embodiments of formula I compounds, R₄ is fluorine.

In yet other embodiments of formula I compounds, R_(g) is hydrogen,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine, chlorine or bromine. Incertain embodiments of formula I compounds, R_(g) is hydrogen, C₁-C₃alkyl or fluorine. In other embodiments of formula I compounds, R_(g) isC₁-C₃ alkyl or fluorine. When R_(g) is C₁-C₃ alkyl, it is methyl, ethyl,or C₃ alkyl, or any combination or subcombination thereof.

In certain embodiments of formula I compounds, each R_(a) isindependently selected from the group consisting of H, C₁-C₃ alkyl,C₁-C₃ fluoroalkyl, phenyl (optionally substituted with 1-3 groupsselected from fluorine, chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH),OH, OC₁₋₃alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃,and O(SO₂)NR₁R₂, or two adjacent Ra together form:

In certain embodiments of formula I compounds, each R_(a) isindependently selected from H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, or phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, fluorine,chlorine. In other embodiments of formula I compounds, an R_(a) ispositioned ortho or para to the bond attached to D. In some embodimentsof formula I compounds, R_(a) is —OCH₃ attached para to the bondattached to D. In some embodiments of formula I compounds, R_(a) ismethyl attached ortho to the bond attached to D. In certain otherembodiments of formula I compounds, two adjacent R_(a) together form:

In embodiments where two adjacent R_(a) together form:

any other R_(a) are each independently selected from hydrogen, halogen,OH, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, and O(SO₂)NR₁R₂.

In certain other embodiments of formula I compounds, X is O, S, CH₂, NHor a bond when B is carbon, or CH₂ or a bond when B is nitrogen. Inother embodiments of formula I compounds, B is carbon and X is O, CH₂,or a bond. In some embodiments when B is carbon, X is O or CH₂.

In some embodiments of formula I compounds, Y and Z are eachindependently selected from CR_(f) or N, and U and V are eachindependently selected from CR_(a) or N. In certain embodiments offormula I compounds, Y is CR_(f). In other embodiments of formula Icompounds, Y is N. In some embodiments of formula I compounds, U isCR_(a). In some embodiments of formula I compounds, Z is CR_(f). In someembodiments of formula I compounds, V is CR_(a). In certain embodimentsof formula I compounds, Y and Z are each CR_(f) and U and V are eachCR_(a).

In certain embodiments of formula I compounds, each R_(f) isindependently H, C₁-C₃ alkyl, fluorine or chlorine. In some embodimentsof formula I compounds, each R_(f) is H.

In yet other embodiments of formula I compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl, or any combination orsubcombination thereof. When W is —CHR′—CHR′—NH—C₁-C₄alkyl, each R′ isindependently methyl, ethyl, C₃ alkyl or hydrogen, or any combination orsubcombination thereof. In certain embodiments of formula I compoundswhen W is —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, each R′ is independentlymethyl, ethyl, C₃ alkyl, or any combination or subcombination thereofwherein 1 to 3 fluoro atoms are attached to the alkyl group. In otherembodiments of formula I compounds when W is—CHR′—CHR′—NH—C₃-C₆cycloalkyl, the C₃-C₆cycloalkyl is cyclopropyl orcyclobutyl. In still other embodiments of formula I compounds when W is—CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl, each R′ is independentlymethyl, ethyl, C₃ alkyl or C₄ alkyl, or any combination orsubcombination thereof, and the C₃-C₆cycloalkyl is cyclopropyl orcyclobutyl. In certain embodiments the C₁-C₄ alkyl is C₁ alkyl. In someother embodiments of formula I compounds, when W is

C₁-C₆alkyl is methyl, ethyl or C₃ alkyl. In yet other embodiments offormula I compounds, when W is

C₁-C₆ alkyl is methyl, ethyl or C₃ alkyl wherein 1 to 3 fluoro atoms areattached to the alkyl group. In some embodiments, W is—CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments W is—CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

in some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₃; in some embodiments, W is—CH₂—CH₂—NH-cyclopropyl; in some embodiments, W is—CH₂—CH₂—NH—CH₂-cyclopropyl.

In some embodiments, the present invention describes compounds orpharmaceutical salts thereof of formula I having the structure offormula II.

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen; C₁-C₁₂ acyl or C₁-C₁₂ acyloxy;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine;

R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine,chlorine or bromine;

X is CH₂ or a bond;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl.

In some embodiments of formula II compounds, W is—CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments of formula II compounds Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments of formula II compoundsW is

in certain embodiments of formula II compounds, W is

In certain embodiments of formula II compounds, X is CH₂.

In still other embodiments of formula II compounds, Y and Z are eachCR_(f) and U and V are each CR_(a).

In some embodiments of formula II compounds, each R_(a) is independentlyselected from H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, phenyl (optionallysubstituted with 1-3 groups selected from fluorine, chlorine, C₁-C₃alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃ alkyl, CN, fluorine, andchlorine.

In some other embodiments of formula II compounds, two adjacent R_(e)together form:

In certain embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₄ is H.In certain other embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.In certain embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In certain embodiments of formula II compounds, two adjacent Re togetherform:

wherein R₃ is hydrogen.

In certain embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₃ is hydrogen and R₄ is hydrogen.

In certain embodiments of formula II compounds, two adjacent R_(e)together form:

wherein R₃ is hydrogen and R₄ is fluorine.

In some embodiments of formula II compounds, each Reis independentlyselected from H and OH.

In other embodiments of formula II compounds, R_(f) is H or fluorine.

In other embodiments of formula II compounds, R_(f) is H.

In yet other embodiments of formula II compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments, one or moreR′ are H.

In some embodiments of formula II compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaII compounds, one or more R′ are H. In other embodiments of formula IIcompounds wherein W contains a C₃-C₆ cycloalkyl moiety, the cycloalkylgroup is C₃-C₄ cycloalkyl.

In still other embodiments of formula II compounds, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

in some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₃; in some embodiments, W is—CH₂—CH₂—NH-cyclopropyl; and in some embodiments, W is—CH₂—CH₂—NH—CH₂-cyclopropyl.

In other embodiments of formula II compounds, R_(g) is hydrogen, C₁-C₃alkyl, or fluorine. In yet other embodiments, R_(g) is methyl; in otherembodiments, R_(g) is fluorine.

In some embodiments of formula II compounds, each R_(f) is H. In otherembodiments of formula II compounds, when R_(f) is H, each Reisindependently selected from H and OH.

In certain other embodiments of formula II compounds, at least one ofR_(a) is OCH₃, fluorine, —OH, —CH₃, or chlorine.

Some embodiments of formula II compounds have the formula IIa, IIb, orIIc:

In certain embodiments, formula II compounds have the formula IId, IIe,or IIf:

In other embodiments, formula II compounds have the formula IIg, IIh, orIIj:

In certain embodiments, the compound of formula II, IIa, IIb, IIc, IId,IIe, IIf, IIg, IIh, or IIj is a pharmaceutically acceptable salt,solvate or prodrug thereof.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt.

In other embodiments, the compound of formula II, IIa, IIb, IIc, IId,IIe, IIf, IIg, IIh, or IIj is a prodrug. In yet other embodiments, thecompound of formula II is the pharmaceutically acceptable salt of theprodrug. In some aspects the pharmaceutically acceptable salt of theprodrug of a compound of Formula II, IIa, IIb, IIc, IId, IIe, IIf, IIg,IIh, or IIj is a hydrochloride salt.

In some embodiments a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, or IIj is described.In other embodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In certain embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

In some embodiments, the present invention describes compounds orpharmaceutical salts thereof of formula I having the structure offormula III:

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen or C₁-C₃ alkyl;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, fluorine or chlorine;

X is O, CH₂, N, S or a bond;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F in some embodiments W is

in certain embodiments, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₃; in some embodiments, W is—CH₂—CH₂—NH-cyclopropyl; in some embodiments, W is—CH₂—CH₂—NH—CH₂-cyclopropyl.

In certain embodiments of formula III compounds, X is O.

In still other embodiments of formula III compounds, Y and Z are eachCR_(f) and U and V are each CR_(a).

In some embodiments of formula III compounds, each R_(a) isindependently selected from H, phenyl, OH, OC₁₋₃ alkyl, fluorine, andchlorine. In yet other embodiments of formula III compounds, each R_(a)is independently selected from H, phenyl, OH, OCH₃, fluorine, andchlorine. In certain embodiments of formula III compounds, R_(a) isindependently selected from H, OCH₃, fluorine, and chlorine. In certainother embodiments of formula III compounds, at least one of R_(a) isOCH₃, fluorine, or chlorine. In some embodiments R_(a) can be C₁₋₃alkyl.

In some other embodiments of formula III compounds, two adjacent R_(e)together form:

In certain embodiments of formula III compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula III compounds, two adjacentR_(e) together form:

wherein R₄ is fluorine.

In certain embodiments of formula III compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula III compounds, two adjacentR_(e) together form:

wherein R₄ is fluorine.

In some embodiments of formula III compounds, each R_(e) isindependently selected from H and OH. In other embodiments, R_(f) is H.In certain embodiments, one or more R′ are H.

In yet other embodiments of formula III compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein one ormore R′ are H or C₁-C₃alkyl. In certain embodiments, one or more R′ areH.

In some embodiments of formula III compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments, one or moreR′ are H. In other embodiments wherein W contains a C₃-C₆ cycloalkylmoiety, the cycloalkyl group is C₃-C₄ cycloalkyl.

In still other embodiments of formula III compounds, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In certain other embodiments of formula III compounds, at least one ofR_(a) is OCH₃, fluorine, or chlorine.

In some embodiments, at least one of R_(a) is —CH₃.

In some embodiments of formula III compounds, each R_(f) is H. In otherembodiments of formula III compounds, when R_(f) is H, each R_(e) isindependently selected from H and OH.

Some embodiments of formula III compounds have the formula IIIa, IIIb,or IIIc:

In certain embodiments, formula III compounds have the formula IId,IIIe, or IIIf:

In certain other embodiments, formula III compounds have the formulaIIIg, IIIh, or IIIj:

In certain embodiments, the compound of formula III, IIIa, IIIb, IIIc,IId, IIIe, or IIIf is a pharmaceutically acceptable salt, solvate orprodrug thereof.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt.

In other embodiments, the compound of formula III is a prodrug. In yetother embodiments, the compound of formula III, IIIa, IIIb, IIIc, IIId,IIIe, or IIIf is the pharmaceutically acceptable salt of the prodrug. Insome aspects the pharmaceutically acceptable salt of the prodrug of acompound of Formula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is ahydrochloride salt.

In some embodiments a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula III, IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is described. Inother embodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In certain embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

In some embodiments, the present invention describes compounds orpharmaceutical salts thereof of formula I having the structure offormula IV:

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen or C₁-C₃ alkyl;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, fluorine or chlorine;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₃; in some embodiments, W is—CH₂—CH₂—NH-cyclopropyl; in some embodiments, W is—CH₂—CH₂—NH—CH₂-cyclopropyl.

In certain embodiments of formula IV compounds, X is CH₂.

In still other embodiments of formula IV compounds, Y and Z are eachCR_(f) and U and V are each CR_(a).

In some embodiments of formula IV compounds, each R_(a) is independentlyselected from H, phenyl, OH, OC₁₋₃ alkyl, fluorine, and chlorine. In yetother embodiments, each R_(a) is independently selected from H, phenyl,OH, OCH₃, fluorine, and chlorine. In certain embodiments, R_(a) isindependently selected from H, OCH₃, fluorine, and chlorine. In certainother embodiments of formula IV compounds, at least one of R_(a) ismethyl, OCH₃, fluorine, or chlorine.

In some other embodiments of formula IV compounds, two adjacent R_(e)together form:

In certain embodiments of formula IV compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula IV compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In certain embodiments of formula IV compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula IV compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In some embodiments of formula IV compounds, each R_(e) is independentlyselected from H and OH. In other embodiments of formula IV compounds,R_(f) is H. In certain embodiments of formula IV compounds, one or moreR′ are H.

In yet other embodiments of formula IV compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaIV compounds, each R′ is independently H.

In some embodiments of formula IV compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaIV compounds, one or more R′ are H. In other embodiments of formula IVcompounds wherein W contains a C₃-C₆ cycloalkyl moiety, the cycloalkylgroup is C₃-C₄ cycloalkyl.

In still other embodiments of formula IV compounds, W is

in some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

wherein each R′ is independently H or C₁-C₃alkyl. In certain embodimentsof formula IV compounds, one or more R′ are H. In some embodiments offormula IV compounds, each R_(f) is H. In other embodiments of formulaIV compounds, when R_(f) is H, each R_(e) is independently selected fromH and OH.

Some embodiments of formula IV compounds have the formula IVa or IVb:

In certain embodiments of formula IV compounds, formula IV compoundshave the formula IVc, IVd, IVe, or IVf

In other embodiments of formula IV compounds, formula IV compounds havethe formula IVg, IVh or IVj:

In certain embodiments, the compound of formula IV, IVa, IVb, IVc, IVd,IVe, IVf, IVg, IVh, or IVj is a pharmaceutically acceptable salt,solvate or prodrug thereof.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt.

In other embodiments, the compound of formula IV, IVa, IVb, IVc, IVd,IVe, IVf, IVg, IVh, or IVj is a prodrug. In yet other embodiments, thecompound of formula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVjis the pharmaceutically acceptable salt of the prodrug. In some aspectsthe pharmaceutically acceptable salt of the prodrug of a compound ofFormula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj is ahydrochloride salt.

In some embodiments, a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula IV, IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, or IVj is described.In other embodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In certain embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

In some embodiments, the present invention describes compounds orpharmaceutical salts thereof of formula I having the structure offormula V:

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, (SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen or C₁-C₃ alkyl;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, fluorine or chlorine;

each Rh is independently selected from hydrogen or CH₃;

X is O, CH₂, N, S or a bond;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl;wherein each R′ is independently H or C₁-C₃ alkyl.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₃; in some embodiments, W is—CH₂—CH₂—NH-cyclopropyl; in some embodiments, W is—CH₂—CH₂—NH—CH₂-cyclopropyl.In certain embodiments of formula V compounds, X is a bond.

In still other embodiments of formula V compounds, Y and Z are eachCR_(f) and U and V are each CR_(a).

In some embodiments of formula V compounds, each R_(a) is independentlyselected from H, phenyl, OH, OC₁₋₃ alkyl, fluorine, and chlorine. In yetother embodiments of formula V compounds, each R_(a) is independentlyselected from H, phenyl, OH, OCH₃, fluorine, and chlorine. In certainembodiments of formula V compounds, R_(a) is independently selected fromH, OCH₃, fluorine, and chlorine. In certain other embodiments of formulaV compounds, at least one of R_(a) is methyl, OCH₃, fluorine, orchlorine.

In some other embodiments of formula V compounds, two adjacent R_(e)together form:

In certain embodiments of formula V compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula V compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In certain embodiments of formula V compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula V compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In some embodiments of formula V compounds, each R_(e) is independentlyselected from H and OH. In other embodiments of formula V compounds,R_(f) is H. In certain embodiments of formula V compounds, one or moreR′ are H.

In yet other embodiments of formula V compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formula Vcompounds, one or more R′ are H.

In some embodiments of formula V compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formula Vcompounds, one or more R′ are H. In other embodiments of formula Vcompounds wherein W contains a C₃-C₆ cycloalkyl moiety, the cycloalkylgroup is C₃-C₄ cycloalkyl.

In still other embodiments of formula V compounds, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

wherein each R′ is independently H or C₁-C₃alkyl. In certain embodimentsof formula V compounds, one or more R′ are H.

In some embodiments of formula V compounds, each R_(f) is H. In otherembodiments of formula V compounds, when R_(f) is H, each R_(e) isindependently selected from H and OH.

Some embodiments of formula V compounds have the formula Va or Vb:

In certain embodiments, formula V compounds have the formula Vc, Vd, Ve,or Vf:

In certain embodiments, the compound of formula V, Va, Vb, Vc, Vd, Ve,Vf, Vg, or Vh is a pharmaceutically acceptable salt, solvate or prodrugthereof.

In certain embodiments, for the compound of formulas V, Va, Vb, Vc, Vd,Ve, Vf, Vg, or Vh, at least one R_(f) is fluoro and in some embodiments,said fluoro is in the 2-position and if both R_(f) are fluoro, they arein the 2,6 positions.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt.

In other embodiments, the compound of formula V, Va, Vb, Vc, Vd, Ve, Vf,Vg, or Vh is a prodrug. In yet other embodiments, the compound offormula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh is the pharmaceuticallyacceptable salt of the prodrug. In some aspects the pharmaceuticallyacceptable salt of the prodrug of a compound of Formula V, Va, Vb, Vc,Vd, Ve, Vf, Vg, or Vh is a hydrochloride salt.

In some embodiments, a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula V, Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh is described. In otherembodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In certain embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

In some embodiments, the present invention describes compounds orpharmaceutical salts thereof of formula I having the structure offormula VI:

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen or C₁-C₃ alkyl;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, fluorine or chlorine;

each Rh is independently selected from hydrogen or CH₃;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In certain embodiments of formula VI compounds, X is a bond.

In still other embodiments of formula VI compounds, Y and Z are eachCR_(f) and U and V are each CR_(a).

In some embodiments of formula VI compounds, each R_(a) is independentlyselected from H, phenyl, OH, OC₁₋₃ alkyl, fluorine, and chlorine. In yetother embodiments of formula VI compounds, each R_(a) is independentlyselected from H, phenyl, OH, OCH₃, fluorine, and chlorine. In certainembodiments of formula VI compounds, R_(a) is independently selectedfrom H, OCH₃, fluorine, and chlorine. In certain other embodiments offormula VI compounds, at least one of R_(a) is methyl, OCH₃, fluorine,or chlorine.

In some other embodiments of formula VI compounds, two adjacent R_(e)together form:

In certain embodiments of formula VI compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula VI compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In certain embodiments of formula VI compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula VI compounds, two adjacent R_(e)together form:

wherein R₄ is fluorine.

In some embodiments of formula VI compounds, each R_(e) is independentlyselected from H and OH. In other embodiments of formula VI compounds,R_(f) is H. In certain embodiments of formula VI compounds, one or moreR′ are H.

In yet other embodiments of formula VI compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaVI compounds, one or more R′ are H.

In some embodiments of formula VI compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaVI compounds, one or more R′ are H. In other embodiments of formula VIcompounds wherein W contains a C₃-C₆ cycloalkyl moiety, the cycloalkylgroup is C₃-C₄ cycloalkyl.

In still other embodiments of formula VI compounds, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

wherein each R′ is independently H or C₁-C₃alkyl. In certain embodimentsof formula VI compounds, one or more R′ are H.

In some embodiments of formula VI compounds, each R_(f) is H. In otherembodiments of formula VI compounds, when R_(f) is H, each R_(e) isindependently selected from H and OH.

Some embodiments of formula VI compounds have the formula VIa or VIb:

In certain embodiments, formula VI compounds have the formula VIc, VId,VIe, VIf, VIg or VIh:

In certain embodiments, the compound of formula VI, VIa, VIb, VIc, VId,VIe, VIf, VIg, or VIh is a pharmaceutically acceptable salt, solvate orprodrug thereof.

In some embodiments, the pharmaceutically acceptable salt of thecompound is an acid addition salt. In other embodiments, the compound offormula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh is a prodrug. Inyet other embodiments, the compound of formula VI, VIa, VIb, VIc, VId,VIe, VIf, VIg, or VIh is the pharmaceutically acceptable salt of theprodrug. In some aspects the pharmaceutically acceptable salt of theprodrug of a compound of Formula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg,or VIh is a hydrochloride salt.

In some embodiments, a pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt or prodrug of a compound ofFormula VI, VIa, VIb, VIc, VId, VIe, VIf, VIg, or VIh is described. Inother embodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In certain embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

In some embodiments, a compound comprising a structure of formula VII isdisclosed

wherein

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen or C₁-C₃ alkyl;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, fluorine or chlorine;

R_(g) is hydrogen, CH₃, F, Cl or CN;

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl.

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

In some embodiments of formula VII compounds, each R_(a) isindependently selected from H, phenyl, OH, OC₁₋₃ alkyl, fluorine, andchlorine. In yet other embodiments of formula VII compounds, each R_(a)is independently selected from H, phenyl, OH, OCH₃, fluorine, andchlorine. In certain embodiments of formula VII compounds, R_(a) isindependently selected from H, OCH₃, fluorine, and chlorine. In certainother embodiments of formula VII compounds, at least one of R_(a) ismethyl, OCH₃, fluorine, or chlorine.

In some other embodiments of formula VII compounds, two adjacent R_(e)together form:

In certain embodiments of formula VII compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula VII compounds, two adjacentR_(e) together form:

wherein R₄ is fluorine.

In certain embodiments of formula VII compounds, two adjacent R_(e)together form:

wherein R₄ is H.

In certain other embodiments of formula VII compounds, two adjacentR_(e) together form:

wherein R₄ is fluorine.

In some embodiments of formula VII compounds, each R_(e) isindependently selected from H and OH. In other embodiments of formulaVII compounds, R_(f) is H. In certain embodiments of formula VIIcompounds, one or more R′ are H.

In yet other embodiments of formula VII compounds, W is—CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaVII compounds, one or more R′ are H.

In some embodiments of formula VII compounds, W is —CHR′—CHR′—NH—C₃-C₆cycloalkyl, or —CHR′—CHR′—NH—C₁-C₄ alkyl-C₃-C₆ cycloalkyl, wherein eachR′ is independently H or C₁-C₃alkyl. In certain embodiments of formulaVI compounds, one or more R′ are H. In other embodiments of formula VIIcompounds wherein W contains a C₃-C₆ cycloalkyl moiety, the cycloalkylgroup is C₃-C₄ cycloalkyl.

In still other embodiments of formula VII compounds, W is

In some embodiments, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃; in some embodiments Wis —CH₂—CH₂—NH—CH₂—CH₂—CH₂F; in some embodiments W is

in certain embodiments, W is

wherein each R′ is independently H or C₁-C₃alkyl. In certain embodimentsof formula VII compounds, one or more R′ are H.

In some embodiments of formula VII compounds, each R_(f) is H. In otherembodiments of formula VII compounds, when R_(f) is H, each R_(e) isindependently selected from H and OH.

In certain embodiments, a compound according to formula I′ is described

wherein:

B is nitrogen or carbon;

D is carbon;

A is a fused ring system selected from:

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, —OPO₃, —OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is hydrogen, C₁-C₁₂ acyl; C₁-C₁₂ acyloxy;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(h) is independently selected from hydrogen or CH₃;

R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine,chlorine or bromine;

each R_(a) is independently selected from: H, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, phenyl (optionally substituted with 1-3 groups selectedfrom fluorine, chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH,OC₁₋₃alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃,O(SO₂)NR₁R₂, or two adjacent R_(a) together form:

X is O, S, CH₂, NH or a bond when B is carbon, or CH₂ or a bond when Bis nitrogen;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N;

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl; or a pharmaceuticallyacceptable salt thereof.

In some embodiments of formula I′, W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃;—CH₂—CH₂—NH—CH₂—CH₂—CH₂F;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound according to formula II′ is described:

each R_(a) is independently selected from H, C₁-C₃ alkyl, phenyl(optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl;

R₁ and R₂ are each independently hydrogen or C₁-C₆ alkyl;

each R₃ is independently hydrogen; C₁-C₁₂ acyl or C₁-C₁₂ acyloxy;

each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine;

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine;

R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN, fluorine,chlorine or bromine;

X is CH₂ or a bond;

Y and Z are each independently selected from CR_(f) or N;

U and V are each independently selected from CR_(a) or N; and

W is —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl;or a pharmaceutically acceptable salt thereof.

In some embodiments formula II′, X is CH₂; Y and Z are each CR_(f); Uand V are each CR_(a); R_(g) is F, C₁ or CH₃; each R_(a) isindependently selected from H, OH, CH₃ and C₁; each R_(f) is H; and W is—CH₂—CH₂—NH—CH₂—CH₂—CH₃, —CH₂—CH₂—NH—CH₂—CH₂—CH₂F,

or a pharmaceutically acceptable salt thereof.

In some embodiments of II′, each R_(e) is independently selected fromhydrogen, OH, or wherein two adjacent R_(e) together form:

and wherein R₃ is H and R₄ is H.

In certain embodiments, a compound having the structure of formula III′is disclosed:

wherein: Q is H or F; Rg is F, Cl, or CH₃; R_(a) is CH₃, Cl or OMe; andRa′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

In some embodiments of III′, Rg is F.

In some embodiments of III′, Rg is F; Ra is CH₃; and Ra′ is H.

In certain embodiments, a compound having the structure IV′ isdisclosed:

wherein: Q is H or F; Rg is F, Cl, or CH₃; Ra is CH₃, Cl or OMe; and Ra′is H, F or OH; or a pharmaceutically acceptable salt thereof.

In some embodiments of IV′, Rg is F.

In certain embodiments of IV′, Rg is F; R_(a) is CH₃; and Ra′ is H.

In some embodiments, a compound of formula V′ is described:

wherein: Q is H or F; Rg is F, Cl, or CH₃; Ra is CH₃, Cl or OMe; and Ra′is H, F or OH; or a pharmaceutically acceptable salt thereof.

In some embodiments of V′, Rg is F.

In some embodiments of V′, Rg is F; Ra is CH₃; and Ra′ is H.

In certain embodiments, a structure of formula VI′ is disclosed:

wherein: Q is H or F; Rg is F, Cl, or CH₃; R_(a) is CH₃, Cl or OMe; andRa′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of VI′ has Rg is F.

In certain embodiments of VI′, Rg is F and R_(a) is CH₃.

In some embodiments of VI′, Rg is F; R_(a) is CH₃; and Ra′ is H.

In some embodiments of a compound of formula VII′ is disclosed:

wherein: Q is H or F; Ra is CH₃, Cl or OMe; and Ra′ is H, F or OH; or apharmaceutically acceptable salt thereof.

In some embodiments of structure VII′, Ra is CH₃ and Ra′ is H.

In certain embodiments, a structure of formula VIII′ is disclosed:

wherein: Q is H or F; Ra is CH₃, Cl or OMe; and Ra′ is H, F or OH; or apharmaceutically acceptable salt thereof.

In some embodiments, formula VIII′, Ra is CH₃ and Ra′ is H.

In certain embodiments, a compound of formula IX′ is described

wherein: Q is H or F; Ra is CH₃, Cl or OMe; and Ra′ is H, F or OH; or apharmaceutically acceptable salt thereof.

In certain embodiments of IX′, R_(a) is CH₃ and Ra′ is H.

In certain embodiments, a compound of formula X′ is described:

wherein: Q is H or F; Ra is CH₃, Cl or OMe; Ra′ is H, F or OH; or apharmaceutically acceptable salt thereof.

In some embodiments of X′, Ra is CH₃ and Ra′ is H.

In some embodiments of compounds of Formulas I through VII and I′through X′, the enantiomeric ratio of the compound is greater than 95:5.In some embodiments, the enantiomeric ratio of the compound is greaterthan 99:1.

Articles of manufacture, which include: packaging material; a compoundof Formula I through VII, I′ through X′, or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, or composition thereof, within the packagingmaterial; and a label that indicates that the compound orpharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, or composition thereof, orcomposition thereof, is used for reducing, diminishing or eliminatingthe effects of estrogen receptors, or for the treatment, prevention oramelioration of one or more symptoms of a disease or condition thatwould benefit from a reduction or elimination of estrogen receptoractivity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

Compounds described herein are synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein. In additions, solvents, temperatures and otherreaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds describedherein are either synthesized or obtained from commercial sources, suchas, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, AlfaAesar, and the like. The compounds described herein, and other relatedcompounds having different substituents are synthesized using techniquesand materials described herein or otherwise known, including those foundin March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey andSundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS3^(rd) Ed., (Wiley 1999). General methods for the preparation ofcompounds can be modified by the use of appropriate reagents andconditions for the introduction of the various moieties found in theformulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following Schemes.

Treatment of 1-1 with bromine followed by reaction withpara-benzyloxyaniline provided 1-4. Subsequent N-alkylation with thebenzylic bromide under basic conditions provided intermediate 1-5.Reduction with LAH gave D-01 (Scheme I).

Reduction of acid 3-1 provided alcohol 3-2, which was protected withTBDMS chloride to provide 3-3. 3-3 was reacted with 1-4 (Scheme I) underbasic conditions to yield 3-5, which was deprotected with TBAF andconverted to the corresponding primary iodide 3-7 with iodine andtriphenylphosphine (Scheme II). Iodide 3-7 was reacted with a variety ofamines, which after debenzylation, resulted in compounds D-02, D-03, andD-08.

Indole 1-4 was reacted with benzyl bromide 3 under basic conditions,resultant 12-5 catalytically deprotected to give 12-6, which was reducedwith LAH to yield D-12 (Scheme III). Alternatively, 1-4 was fluorinated(15-5), and N-benzylated and deprotected (15-6), tosylated (15-7),reacted with cyclopropyamine (15-8) and debenzylated to give D-15.Tosylate 15-7 was also converted with ethylamine and deprotected toyield D-16.

Hydroxybenzaldehyde 13-1 was benzylated to yield 13-2, which wasolefinated to 13-3 with carbon tetrabromide and triphenyl phosphine.13-3 was treated with (4-methoxyphenyl)boronic acid in the presence ofpalladium acetate to yield 13-4, which was chlorinated withN-chlorosuccinimide and subsequently reacted with(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane under basicconditions to provide 13-7. Tosylation to 13-8 followed by reaction withethyl amine to 13-9 and debenzylation resulted in D-13. (Scheme IV).1,1-Dibromo alkene 13-3 was treated with (4-methylphenyl)boronic acid inthe presence of palladium acetate to yield 28-1, which was fluorinatedwith selectifluor and subsequently N-benzylated to give theTBDMS-protected 28-3. After removal of the TBDMS protecting group, 28-4was tosylated to 28-5, reacted with cyclopropylamine to 28-6 anddebenzylated to give D-28. (Scheme IV)

13-3 was treated with (2-methoxyphenyl)boronic acid in the presence of apalladium catalyst to yield 87-2, which was fluorinated withselectifluor and subsequently N-benzylated to give the TBDMS-protected87-4. After removal of the TBDMS protecting group, tosylation to 87-6followed by reaction with propyl amine to 87-7 and debenzylationresulted in D-87. (Scheme IVb).

13-3 was treated with (2,6-dimethylphenyl)boronic acid in the presenceof catalytic palladium to yield 50-1, which was fluorinated withselectifluor and subsequently N-benzylated to give the TBDMS-protected50-3. After removal of the TBDMS protecting group, tosylation to 50-5followed by reaction with cyclobutyl amine to 50-6 and debenzylationresulted in D-50. (Scheme IVc). Intermediate 50-5 was also reacted withethyl amine to 78-1 and subsequent debenzylation resulted in D-78.

13-3 was treated with (2-methyl-4-methoxyphenyl)boronic acid in thepresence of catalytic palladium to yield 52-1, which was fluorinatedwith selectifluor and subsequently N-benzylated to give theTBDMS-protected 52-3. After removal of the TBDMS protecting group,tosylation to 52-5 followed by reaction with cyclopropyl amine to 52-6and debenzylation/demethylation with BBr₃ resulted in D-52. (SchemeIVd). Intermediate 52-2 was N-benzylated to give the TBDMS-protected103-7. After removal of the TBDMS protecting group, tosylation to 103-9followed by reactions with potassium phthalimide and with hydrazine gave103-11. Primary amine 103-11 was reacted with fluoroiodo propane anddebenzylated to yield D-103. Primary amine 103-11 was similarly reactedwith fluoroiodo propane and debenzylated to yield D-104.

1,1-Dibromo alkene 13-3 was treated with(4-fluoro-2-methylphenyl)boronic acid in the presence of palladiumcatalyst to yield 36-1, which was fluorinated with selectifluor andsubsequently N-benzylated to give the TBDMS-protected 36-3. Afterremoval of the TBDMS protecting group, 36-4 was tosylated to 36-5,reacted with cyclopropylamine to 36-6 and debenzylated to give D-36.

Intermediate 96-5 was provided in a sequence similar to that preparing52-5 from 13-3 (see also Scheme IVd). Thereafter, 96-5 was reacted withpropylamine to 96-6 and debenzylated to give D-96 (Scheme IVf).Intermediate 13-3 was treated with (2-phenylphenyl)boronic acid in thepresence of catalytic palladium to yield 66-3, which was fluorinatedwith selectifluor and subsequently N-benzylated to give theTBDMS-protected 66-5. After removal of the TBDMS protecting group,tosylation to 66-7 was followed by reaction with propyl amine to 66-8and debenzylated to yield D-66. (Scheme IVf).

Tosylate 28-5 (see Scheme IV) was treated with ethyl amine to give 29-1,which was catalytically debenzylated to yield D-29. (Scheme V).Similarly, 28-5 was treated with cyclopropylmethylamine, cyclobutylamine, propyl amine or butyl amine, followed by catalytic debenzylationto provide D-39, D-46, D-67, and D-68, respectively.

Tosylate 28-5 (see Scheme IV) was reacted with potassium phthalimide andsubsequently with hydrazine to give 69-7. Primary amine 69-7 was reactedwith fluoroiodo propane and debenzylated to yield D-69. Primary amine69-7 was similarly reacted with fluoroiodo ethane and debenzylated toyield D-70. Intermediate 28-2 was N-alkylated withpara-bromomethylphenylacetic acid 32-2 followed by reaction withN-methyl-N-methoxyamine to prepare 32-3. Compound 32-3 was treated withmethyl magnesium bromide and the resultant ketone 32-4 reacted withcyclopropylamine and debenzylated to D-32.

Compound 40-1 was N-benzylated to give the TBDMS-protected 40-2. Afterremoval of the TBDMS protecting group, tosylation to 40-4 followed byreaction with cyclopropylmethyl amine, cyclopropyl amine or ethyl aminefollowed by catalytic removal of the benzyl protecting group led toD-40, D-33, and D-34, respectively. (Scheme VI).

1,1-Dibromo alkene 13-3 was treated with (2-chlorophenyl)boronic acid inthe presence of palladium catalyst to yield 37-1, which was fluorinatedwith selectifluor and subsequently N-benzylated to give theTBDMS-protected 37-3. After removal of the TBDMS protecting group, 37-4was tosylated to 37-5, reacted with cyclopropylamine to 37-6 anddebenzylated to give D-37.

Compound 85-1 was N-sulfonylated and subsequently reduced with hydrazineto yield indazolamine 85-3. After aromatic iodination withN-iodosuccinimide, compound 85-4 was acetylated with trifluoroaceticanhydride, giving rise to 85-5. Arylation/cyclization of 85-5 gave 85-6,which was fluorinated with selectifluor and subsequently N-benzylated togive the TBDMS-protected 85-8. After removal of the TBDMS protectinggroup, 85-9 was tosylated to 85-10, reacted with ethylamine to 85-11 anddebenzylated to give D-85.

In similar fashion, 85-10 was reacted with cyclopropylmethylamine,cyclobutyl amine, cyclopropyl amine, and propylamine, which, afterdesulfonylation in the presence of basic methanol/water, gave to D-88,D-89, D-90, and D-91 respectively.

85-10 was also reacted with potassium phthalimide, and subsequently,with hydrazine to give 101-12. Primary amine 101-12 was reacted witheither fluoroiodo ethane or fluoroiodopropane and thereafterdesulfonyled in the presence of basic methanol/water to provide,respectively, D-101 and D-102.

Compound L18-1 was arylated in the presence of palladium acetate andresultant ketone L18-2 was converted to the corresponding vinylicbromide with PBr₃. Compound L18-3 was arylated with2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol togive L18-4, which was tosylated to L18-5 and reacted with ethylamine toL18-6. Reduction of the tetrasubstituted double bond in L18-6 gave thecis compound L18-7, which was demethylated to LA-18 with BBr₃. (SchemeIX) L18-5 was also treated with cyclopropylmethylamine followed byreduction and demethylation to yield LA-19.

Compound L18-1 was arylated (2-methyl-bromobenzene) in the presence ofpalladium acetate and resultant ketone L21-2 was converted to thecorresponding vinylic bromide with PBr₃. Compound L21-3 was arylatedwith 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-olto give L21-4, which was tosylated to L21-5 and reacted with ethylamineto L21-6. Reduction of the tetrasubstituted double bond in L21-6 gavethe cis compound L21-7, which was demethylated to LA-21 with BBr₃.(Scheme IXb) L21-5 was also treated with cyclopropylmethylamine followedby reduction and demethylation to yield LA-22.

Compound L18-1 was arylated (4-isopropyl-bromobenzene) in the presenceof palladium acetate and resultant ketone L31-2 was converted to thecorresponding vinylic bromide with PBr₃. Compound L31-3 was arylatedwith 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-olto give L31-4, which was tosylated to L31-5 and reacted with ethylamineto L31-6. Reduction of the tetrasubstituted double bond in L31-6 gavethe cis compound L31-7, which was demethylated to LA-31 with BBr₃.(Scheme IXc) L31-5 was also treated with cyclopropylmethylamine followedby reduction and demethylation to yield LA-33.

Compound T05-1 was alkylated with 2-bromo-1,1-diethoxyethane andsubsequently cyclized in the presence of Lewis acid to the correspondingbenzo{b}thiophene T05-3. After bromination with NBS, the heteroarylbromide was coupled with o-tolylboronic acid in the presence of apalladium catalyst to yield T05-6. Bromination followed by oxidation ofthe sulfur atom led to T05-8. Displacement of the bromide with parahydroxyethylphenol and tosylation of the hydroxyethyl functionality gaveT05-10. Intermediate T05-10 was treated with cyclopropylamine followedby reduction of the sulfonyl group and demethylation to yield BT-05.(Scheme X). In similar fashion, Intermediate T05-10 was treated withcyclopropylmethylamine followed by reduction of the sulfonyl group anddemethylation to yield BT-12.

Displacement of the bromide with para hydroxybenzaldehyde, subsequentreduction of the aldehyde with LAH, and conversion of the resultantbenzylic alcohol with phosphorus tribromide yielded benzylic bromideT17-4. Wittig olefination of T17-4 with tert-butyl3-oxoazetidine-1-carboxylate in the presence of triphenylphosphine ledto T17-5. Removal of the Boc protecting group with acid gave T17-6,which was alkylated with propanal in the presence of sodiumtriacetoxyborohydride to form T17-7. Penultimate intermediate T17-7 wasdemethylated to give BT-17. (Scheme XI)

O-Alkylation of meta-methoxyphenol under basic conditions gave X6-2,which was de-esterified using LiOH and subsequently cyclized withEaton's reagent to produce X6-4. Coupling of X6-4 with 2-bromotoluene inthe presence of palladium acetate led to ketone X6-5, which was treatedwith a Grignard reagent formed from(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane to yield primaryalcohol X6-7 after dehydration and loss of the protecting group withacid. After tosylation of the alcohol, tosylate was displaced withcyclopropylamine and demethoxylated to give BX-06 (Scheme XII). Insimilar fashion, tosylate X6-8 was reacted with ethylamine anddemethoxylated with BBr3 to produce BX-07.

Examples

Materials: all chemicals were reagent grade and used without furtherpurification. Chromatographic elution solvent systems are reported asvolume:volume ratios. LC-MS data were obtained using a LC ThermoFinnigan Surveyor-MS Thermo Finnigan AQA in either positive mode ornegative mode as described below:

LCMS-Condition 01: Method:-LCMS_X-Select (Formic Acid)

Column: X-Select CSH C18 (4.6*50) mm 2.5u, Mobile Phase: A.0.1% Formicacid in water B. 0.1% Formic acid in Acetonitrile, Inj Volume: 5.0 μL,Flow Rate: 1.0. mL/minute, Gradient program: 2% B to 98% B in 2.8minute, Hold till 4.8 min, At 5.0 min B conc is 2% up to 7.0 min.

LCMS-Condition 02: Method:-LCMS_X-Bridge (NH₃).

Column: X-Bridge C18 (3.0*50) mm 2.5μ; Mobile Phase: A. 0.05% NH₃ inwater; B. 0.05% NH₃ in Acetonitrile, Inj Volume: 0.2 μL, Flow Rate: 1.0mL/minute; Gradient program: 1% B to 90% B in 1.5 minute, 100% B in 2.5minute, Hold till 2.8 minute, At 3.0 minute B conc is 1% up to 4.0 min.

LCMS-Condition 03: Method:-LCMS_X-Select (Ammonium Bicarbonate)

Column: X-Select CSH C18 (3.0*50) mm 2.5u; Mobile Phase: A: 5 mMAmmonium Bicarbonate) in water; B: Acetonitrile; Inj Volume: 2 μL, FlowRate: 1.2 mL/minute; Column oven temp. 50 C; Gradient program: 0% B to98% B in 2.0 minute, hold till 3.0 min, at 3.2 min B conc is 0% up to4.0 min.

1-(4-(2-(Ethylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol(D-01)

To 1-(4-methoxyphenyl)propan-1-one 1-1 (5 g, 30.45 mmol) in diethylether (50 mL) was added bromine (1.72 mL, 33.49 mmol) drop wise at 0° C.and stirred at room temperature for 2 h. After completion of thereaction, the reaction mixture was quenched with saturated Na₂S₂O₃solution and extracted with diethyl ether (3×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-40% ethyl acetate in n-hexane to afford4.5 g (61% yield) of compound 1-2 as off white solid.

LCMS-Condition 01: [M+H]⁺=242.90; Rt=3.08 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.03 (d, J=8.80 Hz, 2H), 7.07 (d, J=8.80Hz, 2H), 5.78 (q, J=6.36 Hz, 1H), 3.86 (s, 3H), 1.76 (d, J=6.36 Hz, 3H).

To 2-bromo-1-(4-methoxyphenyl)propan-1-one 1-2 (3 g, 12.34 mmol) in DMF(30 mL) was added 4-(benzyloxy)aniline (3.68 g, 18.51 mmol) at roomtemperature and degassed with argon for 15 min. The reaction mixture wasthen heated at 150° C. for 3 h. After completion of the reaction, thereaction mixture was cooled to room temperature, quenched with water andextracted with ethyl acetate (3×). Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 2.60 g (61% yield) ofcompound 1-4 as off white solid.

LCMS-Condition 01: [M+H]⁺=343.05; Rt=3.65 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.88 (s, 1H), 7.57 (d, J=8.31 Hz, 2H),7.49 (d, J=7.34 Hz, 2H), 7.37-7.42 (m, 3H), 7.22 (d, J=8.80 Hz, 1H),7.04-7.09 (m, 4H), 5.12 (s, 2H), 3.81 (s, 3H), 2.33 (s, 3H).

To 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 1-4 (1.50 g,4.367 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 524 mg, 13.10 mmol) portion wise and stirred for 30min. To the resulting solution at 0° C. was added2-(4-(bromomethyl)phenyl)-N-ethylacetamide (1.23 g, 4.803 mmol). Thereaction mixture was further stirred at room temperature for 18 h. Aftercompletion of the reaction, the reaction mixture was quenched with icecold water, extracted with ethyl acetate (3×). Combined organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-40% ethyl acetate in n-hexane to afford1.3 g (57% yield) of compound 1-5 as off white solid.

LCMS-Condition 01: [M+H]⁺=519.30; Rt=3.28/3.66 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J=8.80 Hz, 1H), 7.85 (t, J=5.14Hz, 1H), 7.46-7.53 (m, 2H), 7.39-7.44 (m, 2H), 7.37 (d, J=5.38 Hz, 1H),7.31 (d, J=8.31 Hz, 2H), 7.25-7.27 (m, 1H), 7.05-7.10 (m, 2H), 6.88 (dd,J=2.45, 8.80 Hz, 1H), 6.80 (dd, J=2.45, 8.80 Hz, 1H), 6.76 (d, J=7.83Hz, 1H), 6.72 (d, J=8.31 Hz, 1H), 6.36 (d, J=7.83 Hz, 1H), 5.16-5.21 (m,2H), 5.12 (s, 2H), 3.86 (s, 3H), 3.79 (s, 2H), 2.95-3.03 (m, 2H), 2.49(s, 3H), 0.91-1.00 (m, 3H).

To2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-ethylacetamide1-5 (400 mg, 0.771 mmol) in THE (20 mL) at 0° C. was added lithiumaluminium hydride (292 mg, 7.712 mmol) portion wise. The reactionmixture was further heated to 70° C. for 24 h. After completion of thereaction, the reaction mixture was cooled to room temperature, quenchedwith saturated Na₂SO₄ solution and extracted with ethyl acetate (3×).Combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bypreparative HPLC purification to afford 16 mg (5% yield) of D-01 as offwhite solid.

LCMS-Condition 01: [M+H]⁺=415.05; Rt=2.17 min

¹H NMR (400 MHz, CD₃OD) δ: 8.44 (br. s, 1H), 7.97 (t, J=9.54 Hz, 1H),7.13 (d, J=8.80 Hz, 2H), 6.99 (d, J=7.83 Hz, 2H), 6.87 (d, J=8.80 Hz,3H), 6.81 (d, J=1.96 Hz, 1H), 6.73 (d, J=7.83 Hz, 2H), 6.53 (dd, J=2.45,8.80 Hz, 1H), 5.07 (s, 2H), 3.72 (s, 3H), 2.94-3.00 (m, 2H), 2.84 (q,J=7.17 Hz, 2H), 2.72-2.78 (m, 2H), 2.07 (s, 3H), 1.13 (t, J=7.34 Hz,3H).

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol(D-02)

To a solution of5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole3-7 (70 mg, 0.119 mmol) and cyclopropanamine (20 mg, 0.357 mmol) in DMF(5 mL) was added triethylamine (0.05 mL, 0.357 mmol) at room temperatureand stirred for 16 h. After completion of the reaction, the reactionmixture was quenched with water and extracted with ethyl acetate (3×).Combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 70 mg (crude) of compound2-2 as light brown solid, which was used as such in the next stepwithout further purification.

LCMS-Condition 01: [M+H]⁺=517.25; Rt=1.85 min

To a solution ofN-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine2-2 (70 mg, 0.135 mmol) in toluene (1 mL) was added trifluoroacetic acid(0.1 mL) at room temperature. The reaction mixture was then heated at90° C. for 16 h. After completion of the reaction, the reaction mixturewas quenched with saturated NaHCO₃ solution and extracted with DCM (3×).Combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bypreparative HPLC column chromatography to afford 6 mg (10% yield) ofD-02 as off white solid.

LCMS-Condition 01: [M+H]⁺=427.05; Rt=1.40 min

¹H NMR (400 MHz, CDCl₃) δ: 7.24 (d, J=8.80 Hz, 2H), 7.06 (d, J=8.31 Hz,2H), 6.98-7.01 (m, 2H), 6.93 (d, J=8.80 Hz, 2H), 6.87 (d, J=8.31 Hz,2H), 6.70 (dd, J=2.45, 8.80 Hz, 1H), 5.14 (s, 2H), 3.84 (s, 3H),2.90-2.96 (m, 2H), 2.73-2.80 (m, 2H), 2.22 (s, 3H), 2.10-2.18 (m, 1H),0.43-0.47 (m, 2H), 0.38-0.43 (m, 2H).

1-(4-(2-((Cyclopropylmethyl)amino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol(D-03)

To 2-(4-(bromomethyl)phenyl)acetic acid (20 g, 87.30 mmol) in THE (200mL) at 0° C. was added borane-dimethyl sulfide (12.4 mL, 130.96 mmol)drop wise. The reaction mixture was stirred at room temperature for 3 h.After completion of the reaction, the reaction mixture was cooled to 0°C. and quenched with dropwise addition of methanol. The resultingreaction mixture was concentrated under reduced pressure and the solidobtained was filtered and washed with n-hexane to afford 14 g ofcompound 3-2 as off white solid which was used as such in the next stepwithout further purification.

¹H NMR (400 MHz, CDCl₃) δ: 7.35 (d, J=7.83 Hz, 2H), 7.21 (d, J=7.83 Hz,2H), 4.49 (s, 2H), 3.86 (t, J=6.36 Hz, 2H), 2.87 (t, J=6.60 Hz, 2H)

To 2-(4-(bromomethyl)phenyl)ethan-1-ol 3-2 (1 g, 4.649 mmol) in DCM (15mL) at 0° C. was added imidazole (0.77 mL, 13.94 mmol) and stirred for15 min. To the resulting solution was added tert-butyldimethylsilylchloride (840 mg, 5.579 mmol) at the same temperature. The reactionmixture was then stirred at room temperature for 16 h. After completionof the reaction, the reaction mixture was quenched with water andextracted with DCM (3×). Combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-30% ethyl acetate in n-hexane to afford 1.2 g (78% yield) of compound3-3 as colourless oil.

¹H NMR (400 MHz, CDCl₃) δ: 7.32 (d, J=7.82 Hz, 2H), 7.20 (d, J=7.82 Hz,2H), 4.51 (s, 2H), 3.81 (t, J=7.09 Hz, 2H), 2.83 (t, J=7.09 Hz, 2H),0.88 (s, 9H), 0.02 (s, 6H).

To 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-4 (470 mg,1.368 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 109 mg, 2.737 mmol) portion wise and stirred for 30min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane 3 (584 mg, 1.779mmol) at the same temperature. The reaction mixture was further stirredat room temperature for 3 h. After completion of the reaction, thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-30% ethyl acetate in n-hexane to afford 660 mg (81% yield) of 3-5 asbrown liquid.

LCMS-Condition 01: [M+H]⁺=592.30; Rt=2.86 min

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole3-5 (650 mg, 1.098 mmol) in THE (5 mL) was added 1M solution oftetrabutylammonium fluoride in THF (1.3 mL, 1.317 mmol) drop wise atroom temperature and stirred for 1 h. After completion of the reaction,the reaction mixture was quenched with saturated NaHCO₃ solution andextracted with ethyl acetate. Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-40% ethyl acetate in n-hexane to afford 425 mg (81% yield) ofcompound 3-6 as off white solid.

LCMS-Condition 01: [M+H]⁺=478.15; Rt=2.32 min

¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=7.34 Hz, 2H), 7.39 (t, J=7.58 Hz,2H), 7.32 (d, J=7.34 Hz, 1H), 7.22-7.25 (m, 3H), 7.15 (d, J=1.96 Hz,1H), 7.08 (d, J=7.83 Hz, 2H), 7.04 (d, J=8.80 Hz, 1H), 6.92-6.96 (m,2H), 6.90 (d, J=8.31 Hz, 2H), 5.16 (s, 2H), 5.13 (s, 2H), 3.84 (s, 3H),3.79-3.83 (m, 2H), 2.80 (t, J=6.36 Hz, 2H), 2.25 (s, 3H).

To a solution of triphenylphosphine (1.15 g, 4.396 mmol) in DCM (30 mL)at 0° C. was added imidazole (300 mg, 4.396 mmol) and iodine (1.11 g,4.396 mmol). The reaction mixture was allowed to attain room temperatureand stirred for 1 h. To the resulting solution was added2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)ethan-1-ol3-6 (420 mg, 0.879 mmol) and stirred at room temperature for 16 h. Aftercompletion of the reaction, the reaction mixture was quenched with waterand extracted with DCM (3×). Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 425 mg (82% yield) ofcompound 3-7 as off white solid.

LCMS-Condition 01: [M+H]⁺=588.05; Rt=2.55 min

¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=7.83 Hz, 2H), 7.39 (t, J=7.34 Hz,2H), 7.29-7.34 (m, 1H), 7.22 (d, J=8.80 Hz, 2H), 7.14 (d, J=2.45 Hz,1H), 7.02-7.06 (m, 3H), 6.85-6.95 (m, 5H), 5.14 (br. s, 2H), 5.13 (br.s, 2H), 3.84 (s, 3H), 3.26-3.32 (m, 2H), 3.06-3.14 (m, 2H), 2.24 (s,3H).

To a solution of5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole3-7 (200 mg, 0.340 mmol) and cyclopropylmethanamine (72 mg, 1.021 mmol)in DMF (5 mL) was added triethylamine (0.14 mL, 1.021 mmol) at roomtemperature and stirred for 16 h. After completion of the reaction, thereaction mixture was quenched with water and extracted with ethylacetate (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-5% methanol in DCM to afford 80 mg (44% yield) of compound 3-8 aslight brown solid.

LCMS-Condition 01: [M+H]⁺=531.30; Rt=1.85 min

¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J=7.34 Hz, 2H), 7.38-7.41 (m, 1H),7.36 (d, J=4.40 Hz, 1H), 7.30-7.34 (m, 1H), 7.22 (d, J=8.80 Hz, 2H),7.14 (d, J=2.45 Hz, 1H), 7.07 (d, J=7.83 Hz, 2H), 7.02 (d, J=8.31 Hz,1H), 6.92 (d, J=8.80 Hz, 2H), 6.87 (d, J=8.31 Hz, 3H), 5.13 (s, 2H),5.12 (s, 2H), 3.81 (s, 3H), 3.18 (br. s, 4H), 2.75 (d, J=7.34 Hz, 2H),2.24 (s, 3H), 1.14-1.21 (m, 1H), 0.57-0.64 (m, 2H), 0.32-0.39 (m, 2H).

To2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(cyclopropylmethyl)ethan-1-amine3-8 (100 mg, 0.188 mmol) in toluene (1 mL) was added trifluoroaceticacid (0.1 mL) at room temperature. The reaction mixture was heated at90° C. for 16 h. After completion of the reaction, the reaction mixturewas quenched with saturated NaHCO₃ solution and extracted with DCM (3×).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bypreparative HPLC column chromatography to afford 8 mg (9% yield) of D-03as off white solid.

LCMS-Condition 01: [M+H]⁺=441.25; Rt=1.48 min

¹H NMR (400 MHz, CDCl₃) δ: 8.58 (s, 1H), 7.21 (d, J=8.31 Hz, 2H), 6.99(d, J=1.96 Hz, 1H), 6.89-6.95 (m, 4H), 6.87 (d, J=8.31 Hz, 1H), 6.82 (d,J=7.83 Hz, 2H), 6.68 (d, J=6.85 Hz, 1H), 5.07 (s, 2H), 3.82 (s, 3H),2.99-3.06 (m, 2H), 2.85-2.92 (m, 2H), 2.70 (d, J=7.34 Hz, 2H), 2.21 (s,3H), 0.79-0.90 (m, 1H), 0.56 (d, J=7.34 Hz, 2H), 0.25 (d, J=4.40 Hz,2H).

1-(4-(2-(Isopropylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol(D-08)

To a solution of5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole3-7 (300 mg, 0.510 mmol) and propan-2-amine (90 mg, 1.531 mmol) in DMF(3 mL) was added triethylamine (0.21 mL, 1.531 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was quenchedwith water and extracted with ethyl acetate (3×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-5% methanol in DCM to afford145 mg (55% yield) of compound 8-2 as light brown solid.

LCMS-Condition 01: [M+H]⁺=519.25; Rt=1.77 min

¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J=7.34 Hz, 2H), 7.38 (t, J=7.34 Hz,2H), 7.28-7.34 (m, 1H), 7.23 (d, J=8.80 Hz, 2H), 7.14 (d, J=2.45 Hz,1H), 7.07 (d, J=7.82 Hz, 2H), 7.03 (d, J=8.80 Hz, 1H), 6.93 (d, J=8.80Hz, 2H), 6.87 (d, J=7.82 Hz, 3H), 5.13 (br. s, 2H), 5.12 (s, 2H), 3.83(s, 3H), 3.00-3.05 (m, 1H), 2.87-2.99 (m, 4H), 2.24 (s, 3H), 1.22 (d,J=6.36 Hz, 6H).

ToN-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)propan-2-amine8-2 (30 mg, 0.057 mmol) in THF:EtOAc (1:1) was added palladium hydroxide(5 mg) at room temperature. The reaction mixture was stirred underhydrogen atmosphere at room temperature for 16 h. After completion ofthe reaction, the reaction mixture was filtered through pad of Celite™™and the filtrate was concentrated under reduced pressure. The resultingcrude compound was purified by preparative HPLC to afford 6 mg (40%yield) of D-08 as off white solid.

LCMS-Condition-1: [M+H]⁺=429.30; Rt=1.45 min

¹H NMR (400 MHz, CDCl₃) δ: 8.64 (br. s, 1H), 7.21 (d, J=8.31 Hz, 2H),7.00 (br. s, 1H), 6.90 (d, J=8.31 Hz, 4H), 6.85 (d, J=8.80 Hz, 2H), 6.80(d, J=7.34 Hz, 2H), 6.69 (d, J=7.82 Hz, 1H), 5.05 (s, 2H), 3.82 (s, 3H),2.83-3.23 (m, 6H), 2.20 (s, 3H), 1.09-1.18 (m, 6H).

1-(4-(2-(Cyclohexylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol(D-09)

To a solution of5-(benzyloxy)-1-(4-(2-iodoethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indole3-7 (150 mg, 0.255 mmol) and cyclohexanamine (76 mg, 0.765 mmol) in DMF(3 mL) was added triethylamine (0.10 mL, 0.765 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was quenchedwith water, extracted with ethyl acetate (3×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-5% methanol in DCM to afford105 mg (74% yield) of compound 9-2 as light brown solid.

LCMS-Condition 01: [M+H]⁺=559.35; Rt=1.86 min

To a solution ofN-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenethyl)cyclohexanamine9-2 (100 mg, 0.178 mmol) in EtOAc (20 mL) was added palladium hydroxide(10 mg) at room temperature. The reaction mixture was stirred underhydrogen atmosphere at room temperature for 16 h. After completion ofthe reaction, the reaction mixture was filtered through a pad ofCelite™, filtrate was concentrated. The resulting crude compound waspurified by prep HPLC column chromatography to afford 50 mg (60% yield)of the title compound D-09 as off white solid.

LCMS-Condition 01: [M+H]⁺=469.20; Rt=1.55 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.72 (s, 1H), 7.29 (d, J=7.82 Hz, 2H),7.00-7.08 (m, 4H), 6.82 (s, 1H), 6.76 (d, J=7.82 Hz, 2H), 6.58 (d,J=7.82 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 2.62-2.86 (m, 6H), 2.12 (s,3H), 1.78-1.87 (m, 2H), 1.65 (d, J=11.74 Hz, 2H), 1.54 (d, J=9.29 Hz,2H), 1.02-1.20 (m, 4H).

2-(4-Methoxyphenyl)-3-methyl-1-(4-(2-((2,2,2-trifluoroethyl)amino)ethyl)benzyl)-1H-indol-5-ol(D-12)

To 5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indole 3-4 (1.5 g,4.373 mmol) in DMF (10 mL) at 0° C. was added 60% dispersion of sodiumhydride in oil (420 mg, 17.49 mmol) portion wise and stirred at the sametemperature for 30 min. To the resulting solution was added2-(4-(bromomethyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide (1.62 g,52.47 mmol) in DMF and stirred at room temperature for 16 h. Aftercompletion of the reaction, the reaction mixture was quenched with icecold water and extracted with ethyl acetate (3×). Combined organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The resulting crude compound was purified by silica gel columnchromatography eluting with 0-10% methanol in DCM to afford 510 mg (20%yield) of the compound 12-5 as brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (t, J=5.87 Hz, 1H), 7.44-7.49 (m, 2H),7.38 (t, J=7.58 Hz, 2H), 7.27-7.34 (m, 3H), 7.11-7.18 (m, 2H), 7.04 (dd,J=8.07, 14.92 Hz, 4H), 6.73-6.81 (m, 3H), 5.19 (s, 2H), 5.11 (s, 2H),3.82-3.90 (m, 2H), 3.78 (s, 3H), 3.39 (s, 2H), 2.16 (s, 3H).

To2-(4-((5-(benzyloxy)-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide12-5 (250 mg, 437.1 mmol) in ethyl acetate (40 mL) was added 20%palladium hydroxide on carbon (100 mg, 50% moisture) at roomtemperature. The reaction mixture was stirred under hydrogen atmospherefor 16 h. After completion of the reaction, the reaction mixture wasfiltered through a pad of Celite™ and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 210 mg (99% yield) ofcompound 12-6 as off white sticky solid.

LCMS-Condition-1: [M+H]⁺=483.10; Rt=2.01 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.72 (s, 1H), 7.29 (d, J=8.31 Hz, 2H),7.01-7.09 (m, 5H), 6.82 (d, J=1.96 Hz, 1H), 6.77 (d, J=8.31 Hz, 2H),6.58 (dd, J=1.96, 8.80 Hz, 1H), 5.16 (s, 2H), 3.82-3.89 (m, 2H), 3.79(s, 3H), 3.40 (s, 2H), 2.12 (s, 3H).

To2-(4-((5-hydroxy-2-(4-methoxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenyl)-N-(2,2,2-trifluoroethyl)acetamide12-6 (195 mg, 403.7 mmol) in THE (30 mL) at 0° C. was added lithiumaluminium hydride (46 mg, 1211.1 mmol) portion wise. The reactionmixture was then heated at 70° C. for 16 h. After completion of thereaction, the reaction mixture was cooled and quenched with saturatedNa₂SO₄ solution, filtered through a pad of Celite™ and washed with ethylacetate. The separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by preparative HPLC purification to afford 13 mg (7% yield) ofD-12 as pale yellow solid.

LCMS-Condition-1: [M+H]⁺=469.20; Rt=1.80 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.70 (s, 1H), 7.27 (d, J=8.80 Hz, 2H),6.99-7.07 (m, 5H), 6.79-6.82 (m, 1H), 6.70-6.76 (m, 2H), 6.57 (dd,J=2.20, 8.56 Hz, 1H), 5.14 (s, 2H), 3.78 (s, 3H), 3.13-3.23 (m, 2H),2.70-2.74 (m, 2H), 2.56-2.61 (m, 2H), 2.11 (s, 3H).

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-5-ol(D-15)

To 5-(benzyloxy)-2-(4-methoxyphenyl)-1H-indole 3-4 (1.78 g, 5.410 mmol)in dry Acetonitrile:DMSO (3:2; 20 mL) at −10° C. was added selectfluor(1.53 g, 4.328 mmol) under argon atmosphere. The reaction mixture wasfurther stirred at 0° C. for 2 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in ethyl acetate (100 mL) and washed with water (40 mL)followed by brine (30 mL). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-20% ethyl acetate in n-hexane to afford402 mg (21% yield) of compound 15-5 as off white solid.

LCMS-Condition 01: [M+18]=366.10; Rt=2.24 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.07 (s, 1H), 7.71-7.75 (m, 2H), 7.47 (d,J=6.85 Hz, 2H), 7.39 (t, J=7.34 Hz, 2H), 7.30-7.33 (m, 1H), 7.25 (dd,J=2.45, 8.80 Hz, 1H), 7.07 (d, J=8.80 Hz, 2H), 7.04 (d, J=2.45 Hz, 1H),6.84 (dd, J=2.45, 8.80 Hz, 1H), 5.12 (s, 2H), 3.80 (s, 3H).

To 5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indole 15-5 (590 mg,1.705 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 203 mg, 5.115 mmol) portion wise. The reactionmixture was further stirred at 0° C. for 30 min. To the resultingsolution was added (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane(671 mg, 2.046 mmol). The reaction mixture was stirred at roomtemperature for 18 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-80% ethyl acetate in n-hexane to afford 405 mg (49% yield) ofcompound 15-6 as brownish solid.

LCMS-Condition 01: [M-18]⁺=464.25; Rt=2.34 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.52-7.56 (m, 2H), 7.44-7.51 (m, 4H),7.37-7.42 (m, 2H), 7.19 (d, J=2.45 Hz, 1H), 7.14 (t, J=8.07 Hz, 4H),6.95 (dd, J=2.45, 8.80 Hz, 1H), 6.84 (d, J=8.31 Hz, 2H), 5.36 (s, 2H),5.21 (s, 2H), 4.64 (t, J=5.38 Hz, 1H), 3.87 (s, 3H), 3.55-3.61 (m, 2H),2.69 (t, J=6.85 Hz, 2H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol15-6 (405 mg, 0.842 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.35 mL, 2.526 mmol) followed by p-TsCl (241 mg, 1.263mmol). The reaction mixture was stirred at room temperature for 18 h.After completion of the reaction, the reaction mixture was diluted withCH₂Cl₂ (100 mL) and washed with water (30 mL) and brine (30 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 365 mg (68% yield) ofcompound 15-7 as brown solid.

LCMS-Condition 01: [M+H]⁺=636.35; Rt=2.54 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.63 (d, J=7.83 Hz, 2H), 7.51 (d, J=7.34Hz, 2H), 7.40-7.47 (m, 4H), 7.31-7.39 (m, 4H), 7.18 (d, J=2.45 Hz, 1H),7.11 (d, J=8.31 Hz, 2H), 7.02 (d, J=8.31 Hz, 2H), 6.93 (dd, J=2.20, 9.05Hz, 1H), 6.79 (d, J=7.83 Hz, 2H), 5.33 (s, 2H), 5.18 (s, 2H), 4.18 (t,J=6.36 Hz, 2H), 3.83 (s, 3H), 2.82 (t, J=6.36 Hz, 2H), 2.39 (s, 3H).

To4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 15-7 (170 mg, 0.267 mmol) in acetonitrile (5mL) was added DIPEA (0.81 mL, 1.072 mmol) and cyclopropyl amine (mL,2.670 mmol) in a sealed tube. The reaction mixture was stirred at roomtemperature for 24 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure, washed with n-hexane(2×10 mL) and decanted followed by drying to afford to afford 135 mg(96% yield) of compound 15-8 as white solid.

LCMS-Condition 01: [M+H]⁺=521.31; Rt=1.74 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.47 (d, J=6.85 Hz, 2H), 7.36-7.44 (m, 5H),7.33 (d, J=7.34 Hz, 2H), 7.10-7.14 (m, 1H), 7.05 (t, J=8.80 Hz, 4H),6.88 (d, J=8.80 Hz, 1H), 6.77 (d, J=7.34 Hz, 2H), 5.28 (br. s, 2H), 5.14(s, 2H), 3.80 (s, 3H), 2.67-2.73 (m, 2H), 2.54-2.62 (m, 2H), 2.03 (d,J=2.93 Hz, 1H), 0.31 (d, J=5.87 Hz, 2H), 0.15 (d, J=1.96 Hz, 2H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine15-8 (140 mg, 0.269 mmol) in TFA (0.81 mL) at 0° C. was added methanesulphonic acid (0.13 mL, 2.002 mmol) and triethyl silane (0.41 mL, 2.566mmol) under argon atmosphere. The reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. After completion of thereaction, the reaction mixture was concentrated under reduced pressureand diluted with ethyl acetate (50 mL). Organic layer was washed withsaturated NaHCO₃ (15 mL) followed by brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by preparative HPLC to afford 18 mg (16% yield) ofD-15 as white solid.

LCMS-Condition 01: [M+H]⁺=431.20; Rt=1.46 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.40 (d, J=8.31 Hz, 2H),7.18-7.23 (m, 1H), 7.03-7.08 (m, 4H), 6.82 (d, J=1.96 Hz, 1H), 6.77 (d,J=7.82 Hz, 2H), 6.67 (dd, J=2.20, 9.05 Hz, 1H), 5.24 (s, 2H), 3.80 (s,3H), 2.67-2.74 (m, 2H), 2.56-2.63 (m, 2H), 2.03 (tt, J=3.36, 6.66 Hz,1H), 0.28-0.34 (m, 2H), 0.11-0.17 (m, 2H).

1-(4-(2-(Ethylamino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-5-ol(D-16)

To4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl-4-methylbenzenesulfonate15-7 (175 mg, 0.276 mmol) in acetonitrile (10 mL) was added DIPEA (0.24mL, 1.380 mmol) followed by 2N ethyl amine in THE (1.37 mL, 2.760 mmol)in a sealed tube. The reaction mixture was stirred at room temperaturefor 24 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure, washed with n-hexane (2×10 mL) anddecanted followed by drying to afford to afford 135 mg (95% yield) ofcompound 16-8 as white solid.

LCMS-Condition 01: [M-18]⁺=491.30; Rt=1.76 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54-7.58 (m, 3H), 7.46-7.53 (m, 4H),7.39-7.43 (m, 2H), 7.17-7.23 (m, 4H), 7.15 (s, 1H), 6.97 (dd, J=2.20,9.05 Hz, 1H), 6.91 (d, J=8.31 Hz, 2H), 5.40 (s, 2H), 5.22 (s, 2H), 3.89(s, 3H), 3.03-3.09 (m, 2H), 2.93 (q, J=7.34 Hz, 2H), 2.81-2.87 (m, 2H),1.20 (t, J=7.34 Hz, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethylethan-1-amine16-8 (145 mg, 0.285 mmol) in TFA (1 mL) at 0° C. was added methanesulphonic acid (0.18 mL, 2.772 mmol) and triethyl silane (0.48 mL, 3.005mmol) under argon atmosphere. The reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. After completion of thereaction, the reaction mixture was concentrated under reduced pressureand diluted with ethyl acetate (50 mL). Organic layer was washed withsaturated NaHCO₃ solution (15 mL) followed by brine (15 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by preparative HPLC purification to afford 9mg (7% yield) of D-16 as white solid.

LCMS-Condition 01: [M+H]⁺=419.20; Rt=1.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (br. s, 1H), 7.41 (d, J=8.80 Hz, 2H),7.20 (d, J=8.80 Hz, 1H), 7.06 (dd, J=2.69, 8.56 Hz, 4H), 6.82 (d, J=1.96Hz, 1H), 6.78 (d, J=7.82 Hz, 2H), 6.67 (dd, J=1.96, 8.80 Hz, 1H), 5.24(s, 2H), 3.80 (s, 3H), 2.59-2.73 (m, 5H), 2.56 (d, J=6.85 Hz, 2H), 0.99(t, J=7.09 Hz, 3H).

3-Chloro-1-(4-(2-(ethylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-1H-indol-5-ol(D-13)

To 5-hydroxy-2-nitrobenzaldehyde 13-1 (15 g, 89.82 mmol) in DMF (100 mL)at 0° C. was added potassium carbonate (18.6 g, 134.7 mmol) and benzylbromide (12 mL, 98.80 mmol) under argon atmosphere. The reaction mixturewas then heated at 80° C. for 3 h. After completion of the reaction, thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×). Combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by trituration in n-hexane to afford 22 g(95% yield) of compound 13-2 as off white solid.

LCMS-Condition 01: [M+H]⁺=257.95; Rt=1.94 min

To 5-(benzyloxy)-2-nitrobenzaldehyde 13-2 (20 g, 77.82 mmol) in CH₂Cl₂(200 mL) at 0° C. was added carbon tetrabromide (39 g, 116.7 mmol) andsolution of triphenyl phosphine (60 g, 233.46 mmol) in dry CH₂Cl₂ (50mL) drop wise. The reaction mixture was stirred at room temperature for2 h. After completion of the reaction, the reaction mixture was filteredthrough a silica pad and washed with CH₂Cl₂. The filtrate wasconcentrated under reduced pressure and the crude intermediate wasdissolved in ethanol (200 mL) and SnCl₂ (52 g, 233.46 mmol) was added toit at room temperature. The reaction mixture was then heated to 80° C.and stirred for 2.5 h. After completion of the reaction, the reactionmixture was diluted with ethyl acetate and quenched with solid potassiumcarbonate (100 g), stirred and filtered. The filtrate was washed withbrine (600 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting crude compound was purified bysilica gel column chromatography eluting with 0-30% ethyl acetate inn-hexane to afford 14 g (48% yield) of compound 13-3 as deep brownliquid.

LCMS-Condition 01: [M+H]⁺=383.95; Rt=2.13 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.48 (m, 1H), 7.26-7.41 (m, 5H), 6.97(d, J=2.45 Hz, 1H), 6.80 (dd, J=2.69, 8.56 Hz, 1H), 6.62 (d, J=8.80 Hz,1H), 4.96 (s, 2H), 4.85 (s, 2H).

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (14 g, 36.55 mmol) intoluene (100 mL) was added (4-methoxyphenyl)boronic acid (8.33 g, 54.83mmol), K₃PO₄ (36.5 g, 182.7 mmol) simultaneously at room temperatureunder argon atmosphere and degassed for 10 min. The solution of Pd(OAc)₂(1.5 g, 0.365 mmol) and S-Phos (2 g, 0.731 mmol) in toluene (50 mL)prepared in another flask was degassed with argon for 10 min and addedto the above reaction mixture at room temperature under argonatmosphere. The reaction mixture was heated at 90° C. and stirred for 4h. After completion of the reaction, the reaction mixture was dilutedwith water and extracted with ethyl acetate (3×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-30% ethyl acetate in n-hexaneto afford 4.8 g (40% yield) of compound 13-4 as off white solid.

LCMS-Condition 01: [M+H]⁺=330.00; Rt=2.19 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.23 (s, 1H), 7.74 (d, J=8.80 Hz, 2H),7.46 (d, J=7.34 Hz, 2H), 7.35-7.41 (m, 2H), 7.27-7.32 (m, 1H), 7.24 (d,J=8.80 Hz, 1H), 7.06 (d, J=2.45 Hz, 1H), 7.00 (d, J=8.80 Hz, 2H), 6.77(dd, J=2.45, 8.80 Hz, 1H), 6.65 (d, J=1.5 Hz, 1H), 5.08 (s, 2H), 3.78(s, 3H).

To 5-(benzyloxy)-2-(4-methoxyphenyl)-1H-indole 13-4 (1.75 g, 5.319 mmol)in CH₂Cl₂ (20 mL) at −10° C. was added N-chlorosuccinimide (568 mg,4.255 mmol). The reaction mixture was then stirred at −10° C. for 1 h.After completion of the reaction, the reaction mixture was diluted withCH₂Cl₂ (50 mL), washed with aqueous sodium sulfite solution (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The resulting crude compound was stirred in methanol (2 mL)for 10 min, filtered and dried to afford 825 mg (43% yield) of compound13-5 as off white solid.

LCMS-Condition 01: [M+H]⁺=363.95; Rt=2.30 min.

To 5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indole 13-5 (820 mg,2.525 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 320 mg, 6.756 mmol) portion wise. The reactionmixture was further stirred at 0° C. for 30 min. To the resultingsolution was added (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane(960 mg, 2.929 mmol). The reaction mixture was stirred at roomtemperature for 18 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (3×). Combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The resulting crudecompound was purified by silica gel column chromatography eluting with0-80% ethyl acetate in n-hexane to afford 605 mg (54% yield) of compound13-7 as off white sticky solid.

LCMS-Condition 01: [M+H]⁺=498.10; Rt=2.32 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.50 (m, 2H), 7.31-7.43 (m, 6H),7.04-7.10 (m, 5H), 6.91 (dd, J=2.45, 8.80 Hz, 1H), 6.73-6.78 (m, 2H),5.29 (s, 2H), 5.15 (s, 2H), 3.81 (s, 3H), 3.47-3.54 (m, 2H), 2.61 (t,J=7.09 Hz, 2H).

To2-(4-((5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol13-7 (550 mg, 1.106 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.46 mL, 3.319 mmol) followed by p-TsCl (318 mg, 1.660mmol). The reaction mixture was stirred at room temperature for 18 h.After completion of the reaction, the reaction mixture was diluted withCH₂Cl₂ (100 mL) and washed with water (30 mL) and brine (30 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 590 mg (81% yield) ofcompound 13-8 as off white solid.

LCMS-Condition 01: [M+H]⁺=652.25; Rt=2.57 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.67 (d, J=7.82 Hz, 2H), 7.57 (d, J=7.34Hz, 2H), 7.45-7.51 (m, 4H), 7.40-7.45 (m, 2H), 7.37 (d, J=8.31 Hz, 2H),7.15-7.19 (m, 3H), 7.06 (d, J=7.82 Hz, 2H), 7.01 (dd, J=1.96, 8.80 Hz,1H), 6.83 (d, J=7.82 Hz, 2H), 5.39 (s, 2H), 5.25 (s, 2H), 4.23 (t,J=6.36 Hz, 2H), 3.90 (s, 3H), 2.87 (t, J=6.36 Hz, 2H), 2.44 (s, 3H).

To4-((5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate13-8 (580 mg, 0.891 mmol) in acetonitrile (15 mL) was added 2N ethylamine in THE (4.4 mL, mmol) and DIPEA (0.5 mL, 2.673 mmol) in a sealtube. The reaction mixture was then stirred at room temperature for 24h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure, washed with n-hexane (2×10 mL) anddecanted followed by drying to afford 252 mg (53% yield) of compound13-9 as white solid.

LCMS-Condition 01: [M+H]⁺=525.15; Rt=1.82 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54-7.58 (m, 3H), 7.46-7.53 (m, 4H),7.40-7.45 (m, 2H), 7.15-7.22 (m, 5H), 7.00 (dd, J=2.20, 9.05 Hz, 1H),6.91 (d, J=8.31 Hz, 2H), 5.40 (s, 2H), 5.24 (s, 2H), 3.90 (s, 3H),3.07-3.12 (m, 2H), 2.97 (q, J=7.34 Hz, 2H), 2.83-2.89 (m, 2H), 1.21 (t,J=7.09 Hz, 3H).

To2-(4-((5-(benzyloxy)-3-chloro-2-(4-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethylethan-1-amine13-9 (250 mg, 0.476 mmol) in TFA (1.5 mL) at 0° C. was added methanesulphonic acid (0.25 mL, 3.850 mmol) and triethyl silane (0.75 mL, 4.695mmol) under argon atmosphere. The reaction mixture was stirred at roomtemperature for 2 h under argon atmosphere. After completion of thereaction, the reaction mixture was concentrated under reduced pressureand diluted with ethyl acetate (100 mL). The separated organic layer waswashed with saturated NaHCO₃ (30 mL) followed by brine (30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude compound was purified by preparative HPLC to afford 45 mg (22%yield) of D-13 as white solid.

LCMS-Condition 01: [M+H]⁺=435.20; Rt=1.46 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.32 (s, 1H), 7.39 (d, J=8.80 Hz, 2H), 7.21(d, J=8.80 Hz, 1H), 7.06 (d, J=8.80 Hz, 4H), 6.81 (d, J=2.45 Hz, 1H),6.78 (d, J=7.82 Hz, 2H), 6.65-6.70 (m, 1H), 5.24 (s, 2H), 3.80 (s, 3H),2.75-2.82 (m, 2H), 2.62-2.69 (m, 4H), 1.02 (t, J=7.34 Hz, 3H).

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol(D-28)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (5.5 g, 14.360 mmol)in toluene:ethanol (9:1; 60 mL) was added 2-methyl-phenyl boronic acid(2.54 g, 18.66 mmol) and 2M solution of Na₂CO₃ (4.56 g, 43.08 mmol) atroom temperature under argon atmosphere and the mixture was degassedwith argon for 30 min. To the resulting solution was added Pd(PPh₃)₄(830 mg, 0.718 mmol) and degassing was continued for another 10 min atroom temperature. The reaction mixture was then heated at 90° C. andstirred for 18 h. After completion of the reaction, the reaction mixturewas diluted with water and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude compound waspurified by silica gel column chromatography eluting with 0-15% ethylacetate in n-hexane to afford 2.35 g (52% yield) of compound 28-1 asthick oil.

LCMS-Condition 01: [M+H]⁺=314.10; Rt=2.38 min

¹H NMR (400 MHz, CDCl₃) δ: 8.03 (br. s, 1H), 7.48 (d, J=7.46 Hz, 2H),7.43-7.46 (m, 1H), 7.39 (t, J=7.46 Hz, 2H), 7.22-7.34 (m, 5H), 7.18 (d,J=1.96 Hz, 1H), 6.95 (dd, J=1.90, 8.74 Hz, 1H), 6.51-6.54 (m, 1H), 5.12(s, 2H), 2.49 (s, 3H).

To 5-(benzyloxy)-2-(o-tolyl)-1H-indole 28-1 (2.34 g, 7.667 mmol) in dryACN:DMSO (3:2; 25 mL) at −10° C. was added selectfluor (2.1 g, 6.134mmol) under argon atmosphere. The reaction mixture was then stirred at0° C. for 2 h. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure, the residue was dissolved inethyl acetate (100 mL) and washed with water (40 mL) followed by brine(30 mL). The separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The resulting crudecompound was purified by silica gel column chromatography eluting with0-15% ethyl acetate in n-hexane followed by preparative TLC to afford820 mg (33% yield) of compound 28-2 as off white solid.

LCMS-Condition 01: [M-18]⁺=314.11; Rt=2.38 min

¹H NMR (400 MHz, CDCl₃) δ: 8.04 (s, 1H), 7.47-7.51 (m, 2H), 7.38-7.45(m, 3H), 7.26-7.33 (m, 4H), 7.21-7.25 (m, 1H), 7.16 (d, J=2.45 Hz, 1H),6.95-7.00 (m, 1H), 5.14 (s, 2H), 2.43 (3, 3H).

To 5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indole 28-2 (450 mg, 1.364mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60% dispersionin oil, 163 mg, 4.092 mmol) portion wise. The reaction mixture was thenstirred at 0° C. for 30 min. To the resulting solution was addedtert-butyl(4-(bromomethyl)phenethoxy)dimethylsilane (591 mg, 1.773mmol). The reaction mixture was stirred at room temperature for 2 h.After completion of the reaction, the reaction mixture was quenched withice cold water and extracted with ethyl acetate (3×25 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to afford 902 mg (crude) of compound 28-3 ascolourless thick liquid.

LCMS-Condition 01: [M-18]⁺=562.30; Rt=3.09 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.44-7.48 (m, 2H), 7.35-7.42 (m, 4H),7.28-7.34 (m, 3H), 7.11-7.16 (m, 2H), 7.00 (d, J=7.83 Hz, 2H), 6.88 (dd,J=1.96, 8.80 Hz, 1H), 6.66 (d, J=7.83 Hz, 2H), 5.13 (s, 1H), 5.12 (s,1H), 5.09 (br. s, 1H), 5.07 (br. s, 1H), 3.65 (t, J=6.60 Hz, 2H), 2.61(t, J=6.85 Hz, 2H), 2.09 (s, 3H), 0.76 (s, 9H), −0.13 (s, 6H).

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indole28-3 (900 mg, 1.559 mmol) in THF (10 mL) at 0° C. was added 1M solutionof tetrabutylammonium fluoride in THF (2.3 mL, 2.339 mmol) dropwise atroom temperature and stirred for 2 h. After completion of the reaction,the reaction mixture was concentrated under reduced pressure and dilutedwith ethyl acetate. The separated organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford 780mg (crude) of compound 28-4 as colourless thick liquid which was used assuch in the next step without further purification.

LCMS-Condition 01: [M-18]⁺=448.10; Rt=2.39 min

¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.51 (m, 2H), 7.37-7.43 (m, 2H),7.29-7.35 (m, 3H), 7.22-7.24 (m, 2H), 7.17 (d, J=2.45 Hz, 1H), 7.13 (dd,J=2.20, 9.05 Hz, 1H), 7.04 (d, J=7.83 Hz, 2H), 6.92 (dd, J=2.45, 8.80Hz, 1H), 6.78 (d, J=7.83 Hz, 2H), 5.13 (s, 1H), 5.12 (s, 1H), 5.07 (s,1H), 5.03 (s, 1H), 3.79 (t, J=6.36 Hz, 2H), 3.48 (q, J=6.85 Hz, 1H),2.78 (t, J=6.36 Hz, 2H), 2.19 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol28-4 (750 mg, 1.613 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.67 mL, 4.839 mmol) followed by tosyl chloride (371 mg,1.936 mmol). The reaction mixture was stirred at room temperature for 18h. After completion of the reaction, the reaction mixture was dilutedwith DCM, and washed with water, and brine. Organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-30% ethyl acetate in n-hexane to afford451 mg (45% yield) of compound 28-5 as colourless sticky solid.

LCMS-Condition 01: [M-18]⁺=602.22; Rt=2.62 min

¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J=8.31 Hz, 2H), 7.46-7.50 (m, 2H),7.39-7.42 (m, 1H), 7.38 (s, 2H), 7.30-7.36 (m, 3H), 7.23 (d, J=4.40 Hz,3H), 7.12-7.17 (m, 2H), 6.92 (d, J=7.83 Hz, 3H), 6.72 (d, J=7.83 Hz,2H), 5.12 (s, 1H), 5.11 (s, 1H), 5.07 (s, 1H), 5.01 (s, 1H), 4.12 (t,J=6.85 Hz, 2H), 2.85 (t, J=6.85 Hz, 2H), 2.39 (s, 3H), 2.16 (s, 3H).

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (225 mg, 0.363 mmol) in acetonitrile (5mL) was added DIPEA (0.6 mL, 3.635 mmol) and cyclopropyl amine (208 mg,3.635 mmol) and in a sealed tube. The reaction mixture was stirred atroom temperature for 72 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure, and dilutedwith ethyl acetate. Organic layer was washed with water and brine, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure210 mg (crude) of compound 28-6 as off white solid which was used assuch in the next step without further purification.

LCMS-Condition 01: [M+H]⁺=505.35; Rt=1.48 min

¹H NMR (400 MHz, CDCl₃) δ: 7.46-7.50 (m, 2H), 7.36-7.42 (m, 2H),7.28-7.35 (m, 2H), 7.20-7.23 (m, 2H), 7.13-7.18 (m, 3H), 6.96 (d, J=8.31Hz, 2H), 6.92 (dd, J=2.45, 8.80 Hz, 1H), 6.72 (d, J=7.83 Hz, 2H), 5.12(s, 1H), 5.11 (s, 1H), 5.04 (s, 1H), 4.99 (s, 1H), 3.02-3.07 (m, 2H),2.89-2.95 (m, 2H), 2.35-2.40 (m, 1H), 2.32 (s, 3H), 1.40-1.50 (m, 4H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine28-6 (280 mg, 0.555 mmol) in ethyl acetate:methanol (4:1; 7 mL) wasadded 20% palladium hydroxide on carbon (55 mg, 20% w/w) at roomtemperature. The reaction mixture was stirred under hydrogen atmospherefor 18 h. After completion of the reaction, the reaction mixture wasfiltered through a pad of Celite™ and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 28 mg (12% yield) of D-28 aswhite solid.

LCMS-Condition 01: [M+H]⁺=415.22; Rt=1.52 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 7.27-7.34 (m, 5H), 6.98 (d,J=7.78 Hz, 2H), 6.83 (d, J=2.01 Hz, 1H), 6.69 (dd, J=2.13, 8.91 Hz, 1H),6.64 (d, J=7.78 Hz, 2H), 5.01-5.11 (m, 2H), 2.67-2.69 (m, 2H), 2.55-2.58(m, 2H), 2.07 (s, 3H), 1.99-2.03 (m, 1H), 0.18-0.25 (m, 2H), 0.02-0.08(m, 2H).

3-Fluoro-2-(2-methoxyphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol(D-87)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (15 g, 39.16 mmol) intoluene:ethanol (3:1, 80 mL) was added 2-methoxyphenyl boronic acid(7.73 g, 50.86 mmol) and aq. solution of Na₂CO₃ (12.45 g, 117.45 mmol)simultaneously at room temperature under argon atmosphere and degassedfor 30 min. To the resulting solution was added Pd(PPh₃)₄ (2.26 g, 1.956mmol) and degassing was continued for another 10 min. The reactionmixture was further heated to 90° C. and stirred for 18 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with ethyl acetate (3×50 mL). The combined organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-8% ethyl acetate in n-hexane to afford 5 g(39% yield) of compound 87-2 as sticky solid.

LCMS-Condition-1: [M+H]⁺=329.70; Rt=2.21 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.02 (s, 1H), 7.77 (dd, J=1.47, 7.83 Hz,1H), 7.46-7.49 (m, 2H), 7.39 (t, J=7.34 Hz, 2H), 7.29-7.36 (m, 3H),7.10-7.15 (m, 2H), 7.01-7.07 (m, 1H), 6.79-6.84 (m, 2H), 5.10 (s, 2H),3.93 (s, 3H).

To a solution of 5-(benzyloxy)-2-(2-methoxyphenyl)-1H-indole 87-2 (4.5g, 13.67 mmol) in dry Acetonitrile:DMSO (5:2, 35 mL) at −10° C. wasadded selectfluor (4.84 g, 13.67 mmol) under argon atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was concentrated under reduced pressure, the residue wasdissolved in ethyl acetate (100 mL) and washed with water (40 mL)followed by brine (30 mL). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-5% ethyl acetate in n-hexane followed by preparative TLC toafford 2.2 g (46% yield) of compound 87-3 as brown solid.

LCMS-Condition-1: [M+H]⁺=348.10; Rt=2.29 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.64 (s, 1H), 7.54 (d, J=7.53 Hz, 1H),7.36-7.40 (m, 2H), 7.26-7.33 (m, 3H), 7.21-7.26 (m, 2H), 7.06-7.10 (m,1H), 6.95-6.99 (m, 2H), 6.77 (dd, J=2.13, 8.91 Hz, 1H), 5.04 (s, 2H),3.79 (s, 3H).

To a solution of 5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indole87-3 (1.5 g, 4.319 mmol) in DMF (10 mL) at 0° C. was added sodiumhydride (60% dispersion in oil, 863 mg, 21.58 mmol) portion wise andstirred at 0° C. for 30 min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (1.7 g, 5.182mmol). Then the reaction mixture was stirred at room temperature for 2h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×75 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-4% ethyl acetate in n-hexane to afford 2 g (77% yield) ofcompound 87-4 as thick yellow oil.

LCMS-Condition-1: [M+Na]⁺=618.35; Rt=2.76 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.44 (d, J=7.82 Hz, 2H), 7.37 (t, J=7.58Hz, 2H), 7.29 (d, J=5.87 Hz, 2H), 7.22-7.26 (m, 1H), 7.11-7.18 (m, 2H),7.02-7.05 (m, 1H), 7.00 (d, J=7.34 Hz, 3H), 6.83 (dd, J=2.45, 9.29 Hz,1H), 6.74 (d, J=7.83 Hz, 2H), 5.74 (s, 2H), 5.11 (s, 2H), 3.71 (s, 3H),3.60-3.68 (m, 2H), 2.60 (t, J=6.60 Hz, 2H), 0.76 (s, 9H), −0.13 (s, 6H).

To a solution of5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(2-methoxyphenyl)-1H-indole87-4 (2 g, 3.361 mmol) in THE (20 mL) at 0° C. was added 1M solution oftetrabutylammonium fluoride in THF (5 mL, 5.042 mmol) drop wise at roomtemperature and stirred for 2 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was concentrated underreduced pressure, diluted with water and extracted with ethyl acetate(2×10 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-30% ethylacetate in n-hexane to afford 1.3 g (81% yield) of compound 87-5 ascolorless thick syrup.

LCMS-Condition-1: [M+Na]⁺=504.15; Rt=2.35 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.55 (d, J=7.34 Hz, 2H), 7.47 (t, J=7.34Hz, 2H), 7.36-7.43 (m, 3H), 7.22-7.28 (m, 2H), 7.19 (d, J=2.45 Hz, 1H),7.14 (t, J=7.34 Hz, 1H), 7.09 (d, J=7.83 Hz, 2H), 6.95 (dd, J=2.20, 9.05Hz, 1H), 6.83 (d, J=7.82 Hz, 2H), 5.09-5.14 (m, 4H), 4.63 (t, J=5.14 Hz,1H), 3.81 (s, 3H), 3.54-3.61 (m, 2H), 2.68 (t, J=6.85 Hz, 2H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol87-5 (1.3 g, 2.702 mmol) in CH₂Cl₂ (15 mL) at 0° C. was addedtriethylamine (1.1 mL, 8.108 mmol) followed by tosyl chloride (621 mg,3.243 mmol) and the reaction mixture was stirred at room temperature for3 h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was concentrated under reduced pressure, diluted withwater and extracted with ethyl acetate (2×50 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-10% ethyl acetate in n-hexane to afford1.3 g (76% yield) of compound 87-6 as light brown solid.

LCMS-Condition-1: [M+Na]⁺=658.20; Rt=2.53 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54 (d, J=8.31 Hz, 2H), 7.45 (d, J=8.31Hz, 3H), 7.34-7.40 (m, 2H), 7.27-7.33 (m, 3H), 7.24 (d, J=8.31 Hz, 2H),7.12-7.19 (m, 1H), 7.10 (d, J=1.96 Hz, 1H), 7.04 (t, J=7.34 Hz, 1H),6.91 (d, J=7.82 Hz, 2H), 6.86 (dd, J=2.20, 9.05 Hz, 1H), 6.71 (d, J=7.82Hz, 2H), 5.12 (s, 2H), 5.08 (s, 1H), 5.00 (br. s, 1H), 4.10 (t, J=6.36Hz, 2H), 3.70 (s, 3H), 2.74 (t, J=6.36 Hz, 2H), 2.32 (s, 3H).

To a solution of4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 87-6 (300 mg, 0.472 mmol) in acetonitrile (4mL) was added DIPEA (0.5 mL, 2.834 mmol) and propyl amine (83 mg, 1.417mmol) in a sealed tube. Then the reaction mixture was stirred at roomtemperature for 48 h. After completion of the reaction (monitored by TLCand LCMS), the reaction mixture was concentrated under reduced pressure,diluted with water and extracted with ethyl acetate (2×20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-5% methanol in DCM toafford 200 mg (65% yield) of compound 87-7 as yellow sticky solid.

LCMS-Condition-1: [M+H]⁺=523.30; Rt=1.94 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46 (d, J=7.88 Hz, 3H), 7.39 (t, J=7.63Hz, 2H), 7.27-7.34 (m, 3H), 7.15-7.20 (m, 1H), 7.11 (d, J=1.97 Hz, 1H),7.05-7.08 (m, 1H), 7.03 (d, J=8.37 Hz, 2H), 6.86 (dd, J=2.46, 8.86 Hz,1H), 6.78 (d, J=8.37 Hz, 2H), 5.14 (s, 2H), 4.96-5.13 (m, 2H), 3.73 (s,3H), 2.74-2.81 (m, 2H), 2.62-2.69 (m, 2H), 2.58 (t, J=7.38 Hz, 2H),1.38-1.47 (m, 2H), 1.23 (br. s, 1H), 0.80-0.86 (m, 3H).

To a solution ofN-(4-((5-(benzyloxy)-3-fluoro-2-(2-methoxyphenyl)-1H-indol-1-yl)methyl)phenethyl)propan-1-amine87-7 (200 mg, 0.361 mmol) in ethyl acetate:methanol (1:1; 3 mL) wasadded 20% palladium hydroxide on carbon (100 mg) at room temperature andthe reaction mixture was stirred under hydrogen atmosphere for 18 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was filtered through a pad of Celite™ and washed withethyl acetate. The filtrate was concentrated under reduced pressure andthe crude compound was purified by preparative HPLC to afford 55 mg (16%yield) of D-87 as off white solid.

LCMS-Condition-1: [M+H]⁺=433.20; Rt=1.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (br. s, 1H), 7.43-7.49 (m, 1H), 7.31(dd, J=1.71, 7.58 Hz, 1H), 7.14-7.20 (m, 2H), 6.98-7.07 (m, 3H), 6.81(d, J=2.45 Hz, 1H), 6.74 (d, J=8.31 Hz, 2H), 6.65 (dd, J=2.45, 8.80 Hz,1H), 5.06-5.20 (m, 1H), 4.87-5.02 (m, 1H), 3.72 (s, 3H), 2.53-2.64 (m,4H), 2.41 (t, J=7.09 Hz, 2H), 1.23-1.38 (m, 3H), 0.80 (t, J=7.58 Hz,3H).

1-(4-(2-(Cyclobutylamino)ethyl)benzyl)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-5-ol(D-50)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (5 g, 13.05 mmol) intoluene-ethanol (35:6 mL) was added 2,6-dimethyl-phenyl boronic acid(2.5 g, 16.78 mmol) and solution of Na₂CO₃ (4.1 g, 38.67 mmol) in water(3 mL) simultaneously at room temperature under argon atmosphere anddegassed for 30 min. To the resulting solution was added Pd(PPh₃)₄ (753mg, 0.652 mmol) and degassing was continued for another 10 min at roomtemperature. The reaction mixture was then heated to 90° C. for 18 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was diluted with water and extracted with ethyl acetate(3×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-15% ethylacetate in n-hexane to afford 1 g (24% yield) of compound 50-1 as thickbrown syrup.

LCMS-Condition 01: [M+H]⁺=328.20; Rt=2.38 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.95 (br. s, 1H), 7.45-7.50 (m, 2H), 7.40(t, J=7.34 Hz, 2H), 7.33 (d, J=7.34 Hz, 1H), 7.22 (t, J=7.83 Hz, 2H),7.14 (d, J=7.82 Hz, 3H), 6.80 (dd, J=1.96, 8.80 Hz, 1H), 6.20 (s, 1H),5.11 (s, 2H), 2.11 (s, 6H).

To 5-(benzyloxy)-2-(2,6-dimethylphenyl)-1H-indole 50-1 (1 g, 3.058 mmol)in dry Acetonitrile:DMSO (3:1 mL) at −10° C. was added selectfluor (1.08g, 3.051 mmol) under argon atmosphere. The reaction mixture was furtherstirred at 0° C. for 2 h. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was concentrated under reducedpressure, the residue was dissolved in ethyl acetate (100 mL) and washedwith water (40 mL) followed by brine (30 mL). The separated organiclayer dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-10% ethyl acetate in n-hexanefollowed by preparative TLC to afford 500 mg (52% yield) of the titlecompound 50-2 as brown solid.

LCMS-Condition 01: [M+18]=364.00; Rt=2.49 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.83 (br. s, 1H), 7.48 (d, J=7.34 Hz, 3H),7.36-7.43 (m, 2H), 7.28-7.36 (m, 2H), 7.15-7.26 (m, 4H), 5.14 (s, 2H),2.14 (s, 6H).

To a solution of 5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indole50-2 (500 mg, 1.449 mmol) in DMF (5 mL) at 0° C. was added sodiumhydride (60% dispersion in oil, 145 mg, 6.041 mmol) portion wise andstirred for 30 min. To the resulting solution was addedtert-butyl(4-(chloromethyl)phenethoxy)dimethylsilane (572 mg, 1.738mmol). Then the reaction mixture was stirred at room temperature for 2h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×25 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-10% ethyl acetate in n-hexane to afford500 mg (60% yield) of compound 50-3 as thick oil.

LCMS-Condition 01: [M+H]⁺=594.20; Rt=3.17 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.39-7.49 (m, 4H), 7.28-7.35 (m, 2H),7.14-7.22 (m, 4H), 6.98 (d, J=6.85 Hz, 2H), 6.88 (d, J=9.29 Hz, 1H),6.66 (d, J=6.85 Hz, 2H), 5.15 (s, 2H), 4.95 (s, 2H), 3.73 (t, J=6.85 Hz,2H), 2.70 (t, J=6.36 Hz, 2H), 1.90 (s, 6H), 0.78 (s, 9H), −0.09 (s, 6H).

To a solution of5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indole50-3 (500 mg, 0.842 mmol) in THE (10 mL) was added 1M solution oftetrabutylammonium fluoride in THE (1.25 mL, 4.809 mmol) dropwise atroom temperature and stirred for 1 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withsaturated NaHCO₃ solution and extracted with ethyl acetate (20 mL×3).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-40% ethyl acetate inn-hexane to afford 400 mg (82% yield) of compound 50-4 as off whitesolid.

LCMS-Condition 01: [M-18]⁺=462.50; Rt=2.36 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54 (d, J=6.85 Hz, 3H), 7.43-7.48 (m, 2H),7.36-7.41 (m, 3H), 7.31 (d, J=7.82 Hz, 1H), 7.22 (d, J=7.34 Hz, 2H),7.06 (d, J=7.83 Hz, 2H), 6.72 (d, J=7.82 Hz, 2H), 5.21 (s, 2H), 5.00 (s,2H), 4.59-4.64 (m, 1H), 3.61-3.67 (m, 2H), 2.75-2.81 (m, 2H), 1.98 (s,6H).

To2-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethan-1-ol50-4 (400 mg, 0.834 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.46 mL, 3.366 mmol) followed by tosyl chloride (236 mg,1.248 mmol). Then the reaction mixture was stirred at room temperaturefor 18 h. After completion of the reaction (monitored by TLC and LCMS),the reaction mixture was diluted with CH₂Cl₂. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 400 mg (78% yield) ofcompound 50-5 as colourless sticky oil.

LCMS-Condition 01: [M+H]⁺=634.25; Rt=2.62 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.64 (d, J=7.83 Hz, 2H), 7.54 (d, J=4.89Hz, 2H), 7.43-7.49 (m, 3H), 7.35 (t, J=6.60 Hz, 4H), 7.19-7.24 (m, 3H),6.99 (d, J=7.83 Hz, 3H), 6.69 (d, J=7.82 Hz, 2H), 5.16 (s, 2H), 4.96 (s,2H), 4.15-4.21 (m, 2H), 2.83 (t, J=5.87 Hz, 2H), 2.40 (s, 3H), 1.97 (s,6H).

To4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 50-5 (200 mg, 0.316 mmol) in acetonitrile (2mL) was added 3-methylazetidine hydrochloride (112 mg, 1.577 mmol) andDIPEA (0.4 mL, 2.158 mmol) in a seal tube. The reaction mixture wasfurther stirred at room temperature for 48 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure,washed with ethyl acetate (2×10 mL). The combined organic layer driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude compound was purified by silica gel column chromatographyeluting with 0-10% methanol in CH₂Cl₂ to afford 100 mg (60% yield) ofthe title compound 50-6 as thick oil.

LCMS-Condition 01: [M+H]⁺=533.65; Rt=1.81 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.45-7.51 (m, 3H), 7.40 (t, J=7.58 Hz, 2H),7.31 (dd, J=7.58, 15.89 Hz, 2H), 7.11-7.19 (m, 3H), 6.98-7.04 (m, 2H),6.93 (dd, J=1.96, 8.80 Hz, 1H), 6.67 (d, J=7.83 Hz, 2H), 5.15 (s, 2H),4.95 (s, 2H), 3.19-3.29 (m, 1H), 2.55-2.67 (m, 4H), 2.01-2.12 (m, 2H),1.91 (s, 6H), 1.49-1.74 (m, 5H).

To a solution ofN-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)cyclobutanamine50-6 (100 mg, 0.187 mmol) in ethyl acetate-methanol (1:1, 4 mL) wasadded 20% palladium hydroxide on carbon (25 mg) at room temperature.Then the reaction mixture was stirred under hydrogen atmosphere for 18h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was filtered through a pad of Celite™ and washed withethyl acetate. The filtrate was concentrated under reduced pressure andthe crude compound was purified by preparative HPLC to afford 20 mg (24%yield) of D-50 as off white solid.

LCMS-Condition 01: [M+H]⁺=443.15; Rt=1.61 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (br. s, 1H), 7.37 (dd, J=2.45, 8.80Hz, 1H), 7.27-7.32 (m, 1H), 7.15 (d, J=7.34 Hz, 2H), 6.98 (d, J=7.83 Hz,2H), 6.84 (d, J=1.96 Hz, 1H), 6.72 (dd, J=2.20, 9.05 Hz, 1H), 6.65 (d,J=8.31 Hz, 2H), 4.90 (s, 2H), 3.06-3.12 (m, 1H), 2.52-2.55 (m, 3H),2.00-2.08 (m, 2H), 1.91 (s, 6H), 1.49-1.63 (m, 5H).

2-(2,6-Dimethylphenyl)-1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-1H-indol-5-ol(D-78)

To a solution of4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 50-5 (200 mg, 0.315 mmol) in acetonitrile (0.5mL) was added ethyl amine (2M in THF, 1.57 mL, 3.15 mmol) and DIPEA (326mg, 2.52 mmol) in a sealed tube. Then the reaction mixture was stirredat room temperature for 4 days. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was concentrated underreduced pressure, and the crude compound was purified by silica gelcolumn chromatography eluting with 0-20% ethyl acetate in n-hexane toafford 100 mg (60% yield) of compound 78-1 as semi-solid.

LCMS-Condition 1: [M+H]+=507.30; Rt=1.87 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.45-7.49 (m, 3H), 7.39-7.43 (m, 2H),7.29-7.35 (m, 2H), 7.05-7.19 (m, 5H), 6.91-6.94 (m, 1H), 6.73 (d, J=8.0Hz, 2H), 5.16 (s, 2H), 4.97 (s, 2H), 2.99-3.01 (m, 2H), 2.87 (d, J=7.6Hz, 2H), 2.74-2.79 (m, 2H), 2.28 (br. S, 1H), 1.94 (s, 6H), 1.12 (t,J=7.6 Hz, 3H).

To a solution of2-(4-((5-(benzyloxy)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)-N-ethylethan-1-amine78-1 (100 mg, 0.196 mmol) in ethyl acetate-methanol (1:1; 4 mL) wasadded 20% palladium hydroxide on carbon (25 mg) at room temperature.Then the reaction mixture was stirred under hydrogen atmosphere for 18h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was filtered through a pad of Celite™ and washed withethyl acetate. The filtrate was concentrated under reduced pressure andthe crude compound was purified by preparative HPLC to afford 18 mg (10%yield) of D-78 as off white solid.

LCMS-Condition 1: [M+H]+=417.50; Rt=1.45 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, 1H), 7.38 (dd, J=1.96, 8.80 Hz,1H), 7.26-7.32 (m, 1H), 7.15 (d, J=7.34 Hz, 2H), 6.99 (d, J=7.82 Hz,2H), 6.84 (d, J=1.96 Hz, 1H), 6.72 (dd, J=2.45, 8.80 Hz, 1H), 6.66 (d,J=8.31 Hz, 2H), 4.90 (s, 2H), 2.53-2.68 (m, 6H), 1.91 (s, 6H), 0.95 (t,J=7.09 Hz, 3H).

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-hydroxy-2-methylphenyl)-1H-indol-5-ol(D-52)

To a solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (6 g,15.66 mmol) in toluene-ethanol (1:1, 50 mL) was added2-methyl-4-methoxy-phenyl boronic acid (3.4 g, 20.36 mmol) and saturatedsolution of Na₂CO₃ (5.06 g, 46.99 mmol) simultaneously at roomtemperature under argon atmosphere and degassed for 30 min. To theresulting solution was added Pd(PPh₃)₄ (906 mg, 0.784 mmol) anddegassing was continued for another 10 min at room temperature. Thereaction mixture was then heated at 90° C. and stirred for 18 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was diluted with water and extracted with ethyl acetate (3×50mL). The combined organic layer was washed with water (50 mL), brine (50mL) dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-10% ethyl acetate in n-hexane to afford1.91 g (36% yield) of compound 52-1 as thick brown syrup.

LCMS-Condition 1: [M+H]+=344.10; Rt=2.35 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.08 (s, 1H), 7.52 (t, J=7.09 Hz, 3H),7.45 (t, J=7.34 Hz, 2H), 7.39 (d, J=7.34 Hz, 1H), 7.32 (d, J=8.31 Hz,1H), 7.17 (d, J=2.45 Hz, 1H), 6.97 (d, J=2.45 Hz, 1H), 6.93 (dd, J=2.45,8.80 Hz, 1H), 6.86 (dd, J=2.45, 8.80 Hz, 1H), 6.45 (d, J=1.96 Hz, 1H),5.16 (s, 2H), 3.85 (s, 3H), 2.49 (s, 3H).

To a solution of 5-(benzyloxy)-2-(4-methoxy-2-methylphenyl)-1H-indole52-1 (1.9 g, 5.539 mmol) in dry Acetonitrile:DMSO (4:1, 30 mL) at −10°C. was added selectfluor (1.76 g, 4.98 mmol) under argon atmosphere. Thereaction mixture was then stirred at 0° C. for 2 h. After completion ofthe reaction (monitored by TLC and LCMS), the reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in ethylacetate (100 mL) and washed with water (40 mL) followed by brine (30mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-10% ethyl acetate inn-hexane followed by preparative TLC to afford 790 mg (40% yield) ofcompound 52-2 as brown solid.

LCMS-Condition 1: [M-18]+=344.05; Rt=2.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.84 (s, 1H), 7.45-7.49 (m, 2H), 7.36-7.41(m, 2H), 7.30-7.34 (m, 2H), 7.24 (dd, J=2.22, 8.61 Hz, 1H), 7.06 (d,J=1.97 Hz, 1H), 6.93 (d, J=2.46 Hz, 1H), 6.87 (ddd, J=2.46, 8.86, 10.83Hz, 2H), 5.13 (s, 2H), 3.79 (s, 3H), 2.31 (s, 3H).

To a solution of5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 52-2 (800mg, 2.216 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 320 mg, 6.630 mmol) portion wise and stirred at 0° C.for 30 min. To the resulting solution was addedtert-butyl(4-(chloromethyl)phenethoxy)dimethylsilane (904 mg, 2.756mmol). The reaction mixture was stirred at room temperature for 18 h.After completion of the reaction (monitored by TLC), the reactionmixture was quenched with ice cold water, extracted with ethyl acetate(3×25 mL) and washed with water (50 mL) and brine (20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography eluting with 0-10% ethyl acetate in n-hexane toafford 960 mg (72% yield) of compound 52-3 as brown thick oil.

LCMS-Condition 1: [M+H]⁺=609.86; Rt=2.27 min

¹H NMR (400 MHz, CDCl₃) δ: 7.46-7.50 (m, 2H), 7.37-7.42 (m, 3H),7.15-7.17 (m, 1H), 7.09 (dd, J=2.46, 8.86 Hz, 1H), 7.02 (d, J=7.88 Hz,3H), 6.89 (dd, J=2.46, 8.86 Hz, 1H), 6.83 (d, J=2.46 Hz, 1H), 6.75-6.79(m, 3H), 5.13 (s, 2H), 4.97-5.10 (m, 2H), 3.84 (s, 3H), 3.72 (t, J=7.14Hz, 2H), 2.73 (t, J=6.89 Hz, 2H), 2.17 (s, 3H), 0.85 (s, 9H), 0.01 (s,3H).

To a solution of5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole52-3 (900 mg, 1.477 mmol) in THE (10 mL) was added 1M solution oftetrabutylammonium fluoride in THF (0.58 mL, 0.580 mmol) drop wise atroom temperature and stirred for 1 h. After completion of the reaction(monitored by TLC), the reaction mixture was quenched with saturatedNaHCO₃ solution and extracted with ethyl acetate (3×25 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography eluting with 0-40% ethyl acetate in n-hexane toafford 600 mg (82% yield) of compound 52-4 as colourless sticky oil.

LCMS-Condition 1: [M+H]⁺=496.10; Rt=2.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.49-7.53 (m, 2H), 7.35-7.47 (m, 4H), 7.28(d, J=8.37 Hz, 1H), 7.16 (d, J=1.97 Hz, 1H), 7.06 (d, J=7.88 Hz, 2H),6.98 (d, J=2.46 Hz, 1H), 6.92 (ddd, J=2.46, 5.66, 8.61 Hz, 2H), 6.73 (d,J=7.88 Hz, 2H), 5.79-5.80 (m, 2H), 5.18 (s, 2H), 4.59 (t, J=5.17 Hz,1H), 3.83 (s, 3H), 3.50-3.58 (m, 2H), 2.64 (t, J=6.89 Hz, 2H), 2.12 (s,3H).

To a solution of2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol52-4 (600 mg, 1.212 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.5 mL, 3.597 mmol) followed by tosyl chloride (385 mg,1.816 mmol). The reaction mixture was stirred at room temperature for 18h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was diluted with CH₂Cl₂ (3×30 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford 600 mg (76% yield) of compound 52-5 ascolorless sticky oil.

LCMS-Condition 1: [M+H]⁺=650.25; Rt=2.59 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.57 (d, J=8.31 Hz, 2H), 7.45-7.49 (m, 2H),7.37-7.43 (m, 3H), 7.33 (d, J=6.85 Hz, 1H), 7.26 (dd, J=8.31, 16.63 Hz,3H), 7.11-7.17 (m, 1H), 6.92-6.96 (m, 3H), 6.85-6.91 (m, 2H), 6.66 (d,J=7.82 Hz, 2H), 5.06-5.15 (m, 4H), 4.13 (t, J=6.60 Hz, 2H), 3.78 (s,3H), 2.77 (t, J=5.87 Hz, 2H), 2.34 (s, 3H), 2.06 (s, 3H).

To a solution of4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 52-5 (300 mg, 0.461 mmol) in acetonitrile (3mL) was added DIPEA (0.7 mL, 3.736 mmol) and cyclopropyl amine (0.26 mL,4.61 mmol) at room temperature in a sealed tube. The reaction mixturewas stirred at room temperature for 72 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture wasconcentrated under reduced pressure, washed with ethyl acetate (2×15mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-10% methanolin CH₂Cl₂ to afford 180 mg (73% yield) of compound 52-6 as colourlessoil.

LCMS-Condition 1: [M+H]⁺=535.25; Rt=1.87 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.44-7.49 (m, 2H), 7.36-7.43 (m, 3H),7.31-7.35 (m, 1H), 7.23 (d, J=7.83 Hz, 1H), 7.11 (br. s, 1H), 7.01 (d,J=7.34 Hz, 2H), 6.84-6.93 (m, 3H), 6.68 (d, J=7.83 Hz, 2H), 5.14 (s,2H), 5.03-5.13 (m, 2H), 3.79 (s, 3H), 2.67-2.72 (m, 2H), 2.54-2.61 (m,2H), 2.04 (s, 3H), 2.04-2.07 (m, 1H), 1.23 (br. s, 1H), 0.28-0.35 (m,2H), 0.12-0.19 (m, 2H).

To a solution ofN-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine52-6 (140 mg, 0.261 mmol) in DCM (14 mL) at 0° C. was added BBr₃ (130mg, 0.520 mmol) drop wise. The reaction mixture was stirred at the sametemperature for 30 min. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was quenched with saturated sodiumbicarbonate solution and extracted with DCM (3×15 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by preparativeHPLC to afford 10 mg (10% yield) of D-52 as off white solid.

LCMS-Condition 1: [M+H]⁺=431.25; Rt=1.41 min

¹H NMR (400 MHz, DMSO-d₆) δ: δ 9.63 (s, 1H), 8.98 (s, 1H), 7.24 (d,J=9.29 Hz, 1H), 7.09 (d, J=7.82 Hz, 1H), 7.01 (d, J=7.34 Hz, 2H), 6.81(s, 1H), 6.64-6.74 (m, 5H), 4.96-5.10 (m, 2H), 2.66-2.74 (m, 2H),2.57-2.62 (m, 2H), 2.00-2.07 (m, 1H), 1.98 (s, 3H), 1.07-1.98 (m, 1H),0.09-0.19 (m, 4H).

3-Fluoro-1-(4-(2-((2-fluoroethyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indol-5-ol(D-103)

To 5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 52-2 (2g, 5.540 mmol) in DMF (15 mL) at 0° C. was added 60% dispersion sodiumhydride in oil (1.1 g, 27.66 mmol) portionwise. The reaction mixture wasfurther stirred at 0° C. for 30 min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (2.18 g, 6.643mmol). The reaction mixture was stirred at room temperature for 2 h.After completion of the reaction, the reaction mixture was quenched withice cold water and extracted with ethyl acetate (3×25 mL). The combinedorganic layer dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography eluting with 0-30% ethyl acetate in n-hexane toafford 2 g (60% yield) of compound 103-7 as thick yellow oil.

LCMS-Condition-1: [M+H]⁺=610.25; Rt=3.14 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.45-7.49 (m, 2H), 7.39 (t, J=7.34 Hz, 2H),7.31-7.36 (m, 2H), 7.22 (d, J=8.31 Hz, 1H), 7.11 (d, J=2.45 Hz, 1H),7.03 (d, J=7.83 Hz, 2H), 6.93 (d, J=2.45 Hz, 1H), 6.86 (ddd, J=2.45,5.75, 8.44 Hz, 2H), 6.69 (d, J=7.83 Hz, 2H), 5.14 (s, 2H), 3.79 (s, 2H),3.67 (t, J=6.60 Hz, 2H), 2.63 (t, J=6.85 Hz, 2H), 2.06-2.10 (m, 3H),1.99 (s, 3H), 0.77 (s, 9H), −0.12 (s, 6H).

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole103-7 (2.5 g, 4.099 mmol) in THE (30 mL) at 0° C. was added 1M solutionof tetrabutylammonium fluoride in THF (6.1 mL, 6.149 mmol) dropwise atroom temperature and stirred for 2 h. After completion of the reaction,the reaction mixture was diluted with water and extracted with ethylacetate (3×50 mL). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-30% ethyl acetate in n-hexane to afford 2 g (98% yield) of compound103-8 as brown sticky solid.

LCMS-Condition-1: [M+H]⁺=496.20; Rt=2.49 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.45-7.49 (m, 2H), 7.32-7.42 (m, 4H), 7.24(d, J=8.31 Hz, 1H), 7.12 (d, J=2.45 Hz, 1H), 7.02 (d, J=8.31 Hz, 2H),6.94 (d, J=2.45 Hz, 1H), 6.85-6.91 (m, 2H), 6.69 (d, J=8.31 Hz, 2H),5.14 (s, 2H), 4.56 (t, J=5.38 Hz, 1H), 3.79 (s, 3H), 3.46-3.52 (m, 2H),2.60 (t, J=7.09 Hz, 2H), 2.07 (s, 3H), 1.99 (s, 2H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol103-8 (2 g, 4.036 mmol) in CH₂Cl₂ (30 mL) at 0° C. was addedtriethylamine (1.6 mL, 12.12 mmol) followed by tosyl chloride (928 mg,4.845 mmol). The reaction mixture was stirred at room temperature for 12h. After completion of the reaction, the reaction mixture was dilutedwith water and extracted with CH₂Cl₂ (3×30 mL). The combined organiclayer dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-10% ethyl acetate in n-hexane to afford toafford 2.4 g (90% yield) of compound 103-9 as white sticky solid.

LCMS-Condition-1: [M+H]⁺=650.80; Rt=2.50 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.66 (d, J=8.31 Hz, 2H), 7.54-7.58 (m, 2H),7.46-7.51 (m, 3H), 7.42 (d, J=6.85 Hz, 1H), 7.36 (d, J=7.83 Hz, 2H),7.32 (d, J=8.80 Hz, 1H), 7.22 (d, J=2.45 Hz, 1H), 7.01-7.05 (m, 3H),6.94-7.01 (m, 2H), 6.75 (d, J=7.83 Hz, 2H), 5.22-5.25 (m, 2H), 4.22 (t,J=6.36 Hz, 2H), 3.87 (s, 3H), 3.41 (s, 3H), 2.86 (t, J=6.36 Hz, 2H),2.43 (s, 3H), 2.15 (s, 2H).

To4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 103-9 (1.5 g, 2.309 mmol) in DMF (5 mL) wasadded potassium pthalimide (512 mg, 2.771 mmol) at room temperature. Thereaction mixture was further heated to 80° C. and stirred for 3 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with ethyl acetate (3×50 mL). The combined organic layerdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-10% ethyl acetate in n-hexane to afford1.4 g (98% yield) of compound 103-10 as pale brown solid.

LCMS-Condition-1: [M+H]⁺=625.10; Rt=2.47 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.80-7.85 (m, 4H), 7.45-7.50 (m, 2H), 7.40(t, J=7.34 Hz, 2H), 7.31-7.37 (m, 2H), 7.16 (d, J=8.31 Hz, 1H), 7.11 (d,J=2.45 Hz, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.86-6.91 (m, 2H), 6.82-6.85(m, 1H), 6.66 (d, J=7.83 Hz, 2H), 5.15 (s, 2H), 5.03-5.10 (m, 2H), 3.79(s, 3H), 3.73 (t, J=7.34 Hz, 2H), 2.83 (t, J=7.09 Hz, 2H), 1.99 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)isoindoline-1,3-dione103-10 (1.4 g, 2.241 mmol) in ethanol (15 mL) was added hydrazinehydrate (112 mg, 2.241 mmol) at room temperature. The reaction mixturewas further heated to 80° C. and stirred for 4 h. After completion ofthe reaction, the reaction mixture was filtered, washed with DCM (50 mL)and the filtrate was concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-3% methanol in DCM to afford 828 mg (73% yield) of compound103-11 as white solid.

LCMS-Condition-1: [M+H]⁺=495.25; Rt=1.70 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.07 (dd, J=3.18, 5.62 Hz, 1H), 7.88 (dd,J=3.42, 5.87 Hz, 1H), 7.45-7.50 (m, 2H), 7.30-7.43 (m, 4H), 7.24 (d,J=8.31 Hz, 1H), 7.12 (d, J=2.45 Hz, 1H), 7.02 (d, J=7.83 Hz, 2H), 6.94(d, J=2.45 Hz, 1H), 6.88 (dt, J=2.69, 8.44 Hz, 2H), 6.70 (d, J=7.83 Hz,2H), 5.15 (s, 2H), 5.06-5.12 (m, 2H), 3.79 (s, 3H), 2.69-2.75 (m, 2H),2.56 (t, J=7.34 Hz, 2H), 2.06 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-amine103-11 (300 mg, 0.606 mmol) in acetonitrile (4 mL) was added potassiumcarbonate (83.7 mg, 0.606 mmol) and 1-fluoro-2-iodoethane (105 mg, 0.606mmol) and in a seal tube. The reaction mixture was further stirred atroom temperature for 24 h. After completion of the reaction, thereaction mixture was diluted with water and extracted with ethyl acetate(2×10 mL). The combined organic layer dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-3% methanolin DCM to afford 250 mg (76% yield) of compound 103-12 as colorlesssticky solid.

LCMS-Condition-1: [M+H]⁺=541.35; Rt=1.73 min

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)-2-fluoroethan-1-amine103-12 (250 mg, 0.455 mmol) in ethyl acetate:methanol (1:1; 10 mL) wasadded 20% palladium hydroxide on carbon (75 mg, 20% w/w) at roomtemperature. The reaction mixture was further stirred under hydrogenatmosphere for 1 h. After completion of the reaction, the reactionmixture was filtered through pad of a Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 20 mg (9.6%yield) of D-103 as off white solid.

LCMS-Condition-1: [M+H]⁺=451.25; Rt=1.54 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.01 (s, 1H), 7.24-7.27 (m, 1H), 7.22 (d,J=8.31 Hz, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.92 (d, J=2.45 Hz, 1H), 6.86(dd, J=2.45, 8.31 Hz, 1H), 6.82 (d, J=2.45 Hz, 1H), 6.65-6.70 (m, 3H),4.97-5.12 (m, 2H), 4.47 (t, J=5.14 Hz, 1H), 4.35 (t, J=5.14 Hz, 1H),3.78 (s, 3H), 2.79 (t, J=5.14 Hz, 1H), 2.72 (t, J=5.14 Hz, 1H),2.65-2.70 (m, 2H), 2.55-2.61 (m, 2H), 2.06 (s, 3H).

3-Fluoro-1-(4-(2-((3-fluoropropyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indol-5-ol(D-104)

To a solution of2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-amine103-11 (300 mg, 0.606 mmol) in acetonitrile (4 mL) was added potassiumcarbonate (83.7 mg, 0.606 mmol) and 1-fluoro-3-iodopropane (114 mg,0.606 mmol) in a sealed tube. The reaction mixture was stirred at roomtemperature for 24 h.

After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was diluted with water and extracted with ethyl acetate(2×10 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-3% methanolin DCM to afford 250 mg (74% yield) of compound 104-12 as colourlesssticky solid.

LCMS-Condition-1: [M+H]⁺=555.25; Rt=1.76 min

¹H NMR (400 MHz, DMSO-d6) S: 7.46-7.49 (m, 2H), 7.32-7.42 (m, 4H), 7.24(d, J=8.31 Hz, 1H), 7.12 (d, J=2.45 Hz, 1H), 7.03 (d, J=7.83 Hz, 2H),6.94 (d, J=2.45 Hz, 1H), 6.85-6.91 (m, 2H), 6.70 (d, J=8.31 Hz, 2H),5.02-5.14 (m, 4H), 4.51 (t, J=6.11 Hz, 1H), 4.39 (t, J=5.87 Hz, 1H),3.79 (s, 3H), 2.58-2.73 (m, 6H), 2.06 (s, 3H), 1.70-1.83 (m, 2H).

To a solution ofN-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)-3-fluoropropan-1-amine104-12 (250 mg, 0.458 mmol) in ethyl acetate:methanol (1:1; 10 mL) wasadded 20% palladium hydroxide on carbon (75 mg, 20% w/w) at roomtemperature. The reaction mixture was stirred under hydrogen atmospherefor 12 h. After completion of the reaction (monitored by TLC and LCMS),the reaction mixture was filtered through a pad of Celite™ and washedwith methanol. The filtrate was concentrated under reduced pressure andthe crude compound was purified by preparative HPLC to afford 50 mg (23%yield) of D-104 as off white solid.

LCMS-Condition-1: [M+H]⁺=465.25; Rt=1.88 min

¹H NMR (400 MHz, DMSO-d6) S: 9.01 (s, 1H), 7.24-7.27 (m, 1H), 7.22 (d,J=8.31 Hz, 1H), 7.01 (d, J=8.31 Hz, 2H), 6.92 (d, J=2.45 Hz, 1H), 6.86(dd, J=2.69, 8.56 Hz, 1H), 6.82 (d, J=1.96 Hz, 1H), 6.69 (d, J=1.47 Hz,1H), 6.65-6.68 (m, 2H), 4.97-5.09 (m, 2H), 4.50 (t, J=6.11 Hz, 1H), 4.38(t, J=5.87 Hz, 1H), 3.78 (s, 3H), 2.53-2.64 (m, 6H), 2.06 (s, 3H),1.64-1.78 (m, 2H).

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-5-ol(D-36)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline D-13-3 (15 g, 39.16 mmol)in toluene (60 mL) was added 2-methyl-4-fluoro-phenyl boronic acid (7.2g, 46.96 mmol), Na₂CO₃ (12.4 g, 117.4 mmol) at room temperature anddegassed with argon for 10 min. To the resulting solution was addedPd(PPh₃)₄ (2.25 g, 1.950 mmol) and degassed with argon for another 10min. The reaction mixture was further heated to 90° C. and stirred for18 h. After completion of the reaction, the reaction mixture was dilutedwith water and extracted with ethyl acetate (thrice). The combinedorganic layer dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting crude compound was purified bysilica gel column chromatography eluting with 0-8% ethyl acetate inn-hexane to afford 5 g (38% yield) of compound 36-1 as brown solid

LCMS: [M+H]⁺=333.35; Rt=2.29 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.13 (br. s, 1H), 7.50-7.56 (m, 1H),7.45-7.50 (m, 2H), 7.39 (t, J=7.34 Hz, 2H), 7.26-7.34 (m, 2H), 7.20 (d,J=10.27 Hz, 1H), 7.13 (br. s, 2H), 6.83 (d, J=8.80 Hz, 1H), 6.46 (s,1H), 5.11 (s, 2H), 2.45 (s, 3H).

To a solution of 5-(benzyloxy)-2-(4-fluoro-2-methylphenyl)-1H-indole36-1 (10 g, 30.21 mmol) in dry acetonitrile:DMSO (3:2; 80 mL) at −10° C.was added selectfluor (10.6 g, 30.16 mmol) under argon atmosphere. Thereaction mixture was allowed to attain room temperature and stirred for4 h. After completion of the reaction, the reaction mixture was thereaction mixture was quenched with water and extracted with ethylacetate (3×20 mL). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-5% ethyl acetate in n-hexane to afford 1 g (9.5% yield) ofcompound 36-2 as brown solid.

LCMS: [M+H]⁺=350.30; Rt=2.30 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.01 (br. s, 1H), 7.49-7.55 (m, 3H), 7.44(t, J=7.34 Hz, 2H), 7.37 (d, J=7.34 Hz, 1H), 7.30 (t, J=9.29 Hz, 2H),7.21 (t, J=8.56 Hz, 1H), 7.13 (s, 1H), 6.94 (d, J=8.80 Hz, 1H), 5.18 (s,2H), 2.39 (s, 3H).

To a solution of5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indole 36-2 (400mg, 1.136 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 82 mg, 3.410 mmol) portionwise and stirred for 30min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (487 mg, 1.478mmol). Then the reaction mixture was stirred at room temperature for 18h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×15 mL). The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-4% ethyl acetate in n-hexane to afford 550mg (92% yield) of compound 36-3 as yellowish oil.

LCMS-Condition 01: [M-18]⁺=580.30; Rt=2.87 min

¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, J=7.34 Hz, 2H), 7.37-7.43 (m, 2H),7.32-7.36 (m, 1H), 7.10-7.21 (m, 4H), 7.02 (d, J=8.07 Hz, 2H), 6.84-6.95(m, 2H), 6.74 (d, J=8.07 Hz, 2H), 5.13 (m, 2H), 4.95-5.09 (m, 2H), 3.72(t, J=6.91 Hz, 2H), 2.73 (t, J=6.85 Hz, 2H), 2.15 (s, 3H), 0.87 (s, 9H),0.00 (s, 6H).

To a solution of5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indole36-3 (550 mg, 0.920 mmol) in THF (10 mL) at 0° C. was added TBAF (361mg, 1.380 mmol). The reaction mixture was then stirred at roomtemperature for 1 h. After completion of the reaction (monitored by TLCand LCMS), the reaction mixture was quenched with ice cold water andextracted with ethyl acetate (3×20 mL). The combined organic layer waswashed with water (20 mL) and brine (20 mL) dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The compound waspurified by silica gel column chromatography eluting with 0-50% ethylacetate in n-hexane to afford 500 mg crude of compound 36-4 as yellowishoil.

LCMS-Condition 01: [M-18]⁺=466.05; Rt=2.33 min

¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.50 (m, 2H), 7.28-7.43 (m, 3H),7.18-7.23 (m, 1H), 7.17 (d, J=2.45 Hz, 1H), 7.12-7.15 (m, 1H), 7.05 (d,J=8.31 Hz, 2H), 6.89-7.02 (m, 3H), 6.77 (d, J=7.83 Hz, 2H), 5.14 (s,2H), 4.97-5.13 (m, 2H), 3.77-3.82 (m, 2H), 2.79 (t, J=6.60 Hz, 2H), 2.14(s, 3H).

To a solution of2-(4-((5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol36-4 (500 mg, 1.033 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.43 mL, 3.102 mmol) followed by p-TsCl (256 mg, 1.344mmol) and the reaction mixture was stirred at room temperature for 2 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was diluted with water (30 mL) and extracted with DCM(3×20 mL). The combined organic layer was washed with saturated sodiumbicarbonate solution (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 500 mg (76% yield) ofcompound 36-5 as yellow solid.

LCMS-Condition 01: [M+H]⁺=638.20; Rt=2.51 min

¹H NMR (400 MHz, CDCl₃) δ: 7.63-7.72 (m, 2H), 7.48 (d, J=7.34 Hz, 2H),7.37-7.43 (m, 2H), 7.23 (d, J=7.83 Hz, 2H), 7.08-7.20 (m, 4H), 6.97-7.02(m, 1H), 6.91-6.96 (m, 4H), 6.68-6.75 (m, 2H), 5.13 (s, 2H), 4.94-5.08(s, 2H), 4.13 (t, J=7.09 Hz, 2H), 2.87 (t, J=6.85 Hz, 2H), 2.40 (s, 3H),2.13 (s, 3H).

To a solution of4-((5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 36-5 (250 mg, 0.392 mmol) in acetonitrile (1mL) was added cyclopropanamine (224 mg, 3.920 mmol) and DIPEA (0.68 mL,3.920 mmol) in a sealed tube. The reaction mixture was then stirred atroom temperature for 72 h. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was concentrated under reducedpressure and diluted with ethyl acetate. The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-50% ethyl acetate in n-hexane to afford160 mg (78% yield) of compound 36-6 as off white solid.

LCMS-Condition 01: [M+H]⁺=523.20; Rt=1.85 min

¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=7.34 Hz, 2H), 7.38-7.43 (m, 2H),7.30-7.36 (m, 1H), 7.14-7.22 (m, 3H), 7.03 (d, J=7.83 Hz, 2H), 6.87-7.01(m, 3H), 6.74 (d, J=7.80 Hz, 2H), 5.14 (s, 2H), 4.97-5.09 (m, 2H),2.86-2.92 (m, 2H), 2.70-2.76 (m, 2H), 2.14 (s, 3H), 2.07-2.11 (m, 1H),0.40-0.48 (m, 2H), 0.30-0.39 (m, 2H).

To a solution ofN-(4-((5-(benzyloxy)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine36-6 (160 mg, 0.3061 mmol) in ethyl acetate (5 mL) was added 20%palladium hydroxide on carbon (40 mg) at room temperature. Then thereaction mixture was stirred under hydrogen atmosphere for 18 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was filtered through pad of a Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 28 mg (21%yield) of D-36 as white solid.

LCMS-Condition 01: [M+H]⁺=433.10; Rt=1.54 min

¹H NMR (400 MHz, CDCl₃) δ: 7.18 (dd, J=6.11, 8.07 Hz, 1H), 7.06-7.11 (m,1H), 6.96-7.04 (m, 4H), 6.87-6.94 (m, 1H), 6.70-6.78 (m, 3H), 4.93-5.07(m, 2H), 2.89-2.95 (m, 2H), 2.70-2.76 (m, 2H), 2.12 (s, 3H), 0.81-0.92(m, 1H), 0.44 (d, J=6.36 Hz, 2H), 0.35-0.41 (m, 2H).

3-Fluoro-2-(4-methoxy-2-methylphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol(D-96)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (10 g, 26.10 mmol) intoluene:ethanol (60:20 mL) was added (4-methoxy-2-methylphenyl)boronicacid (5.6 g, 33.94 mmol) and solution of Na₂CO₃ (8.3 g, 78.32 mmol)simultaneously at room temperature under argon atmosphere and degassedfor 30 min. To the resulting solution was added catalyst Pd(PPh₃)₄ (1.5g, 1.305 mmol) and degassed with argon for another 10 min at roomtemperature. The reaction mixture was further heated to 90° C. andstirred for 18 h. After completion of the reaction, the reaction mixturewas diluted with water and extracted with ethyl acetate (3×50 mL). Thecombined organic layer dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude compound waspurified by silica gel column chromatography eluting with 0-20% ethylacetate in n-hexane to afford 3 g (33% yield) of compound 96—as yellowsolid.

LCMS-Condition-1: [M+H]⁺=344.15; Rt=2.24 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.01 (br. s, 1H), 7.44-7.49 (m, 2H), 7.42(d, J=6.36 Hz, 1H), 7.36-7.40 (m, 2H), 7.32 (d, J=7.34 Hz, 1H), 7.26 (d,J=8.80 Hz, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 6.87 (d, J=9.29 Hz, 1H),6.77-6.82 (m, 1H), 6.38 (s, 1H), 5.10 (s, 2H), 3.79 (s, 3H), 2.43 (s,3H).

To 5-(benzyloxy)-2-(4-methoxy-2-methylphenyl)-1H-indole 96-1 (2.5 g,7.288 mmol) in dry Acetonitrile:DMSO (15:5 mL) at −10° C. was addedselectfluor (2.58 g, 7.288 mmol) under argon atmosphere. The reactionmixture was further stirred at room temperature for 4 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with ethyl acetate (3×50 mL). The combined organic layerdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The resulting crude compound was purified by silica gel columnchromatography eluting with 0-5% ethyl acetate in n-hexane to afford 1.2g (46% yield) of compound 96-2 as brown solid.

LCMS-Condition-1: [M-18]⁺=344.05; Rt=2.23 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.85 (s, 1H), 7.48 (d, J=7.34 Hz, 2H),7.40 (t, J=7.58 Hz, 2H), 7.34 (d, J=8.31 Hz, 2H), 7.25 (dd, J=2.20, 9.05Hz, 1H), 7.07 (d, J=1.96 Hz, 1H), 6.94 (s, 1H), 6.88 (ddd, J=2.20, 9.05,11.74 Hz, 2H), 5.14 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H).

To 5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole 96-2(400 mg, 1.108 mmol) in DMF (mL) at 0° C. was added 60% dispersionsodium hydride in oil (110 mg, 2.770 mmol) portionwise. The reactionmixture was further stirred at 0° C. for 30 min. To the resultingsolution was added tert-butyl(4-(bromomethyl)phenethoxy)dimethylsilane(436 mg, 1.329 mmol). The reaction mixture was stirred at roomtemperature for 3 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (3×25 mL). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-8% ethyl acetate in n-hexane to afford__mg (crude) of compound 96-3 asthick oil.

LCMS-Condition-1: [M+Na]⁺=633.25; Rt=3.05 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.42-7.47 (m, 2H), 7.37 (t, J=7.34 Hz, 2H),7.30-7.34 (m, 2H), 7.18-7.23 (m, 1H), 7.10 (d, J=2.45 Hz, 1H), 7.01 (d,J=7.82 Hz, 2H), 6.92 (d, J=2.45 Hz, 1H), 6.81-6.87 (m, 2H), 6.68 (d,J=7.82 Hz, 2H), 5.10-5.13 (m, 2H), 4.98-5.09 (m, 2H), 3.77 (s, 3H), 3.65(t, J=6.85 Hz, 2H), 2.61 (t, J=6.60 Hz, 2H), 2.06 (s, 3H), 0.74-0.78 (m,9H), −0.13 (s, 6H)

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indole96-3 (400 mg, 0.656 mmol) in THE (3 mL) at 0° C. was added 1M solutionof tetrabutylammonium fluoride in THF (0.98 mL, 0.985 mmol) dropwise.The reaction mixture was further stirred at room temperature for 2 h.After completion of the reaction, the reaction mixture was quenched withwater and extracted with ethyl acetate. The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 30% ethyl acetate in n-hexane to afford 280mg (87% yield) of compound 96-4 as yellowish thick oil.

LCMS-Condition-1: [M+H]⁺=496.25; Rt=2.40 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.54-7.59 (m, 2H), 7.41-7.50 (m, 4H), 7.33(d, J=8.31 Hz, 1H), 7.21 (d, J=2.45 Hz, 1H), 7.11 (d, J=8.31 Hz, 2H),7.03 (d, J=2.45 Hz, 1H), 6.94-6.99 (m, 2H), 6.78 (d, J=8.31 Hz, 2H),5.23 (s, 2H), 5.12-5.21 (m, 2H), 4.63-4.68 (m, 1H), 3.88 (s, 3H), 3.58(dt, J=5.38, 7.09 Hz, 2H), 2.66-2.72 (m, 2H), 2.17 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol96-4 (280 mg, 0.565 mmol) in CH₂Cl₂ (3 mL) at 0° C. was addedtriethylamine (0.23 mL, 1.696 mmol) followed by tosyl chloride (129 mg,0.678 mmol). The reaction mixture was stirred at room temperature for 18h. After completion of the reaction, the reaction mixture was dilutedwith CH₂Cl₂ (3×30 mL). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-10% ethyl acetate in n-hexane to afford 310 mg (84% yield) of compound96-5 as off white solid.

LCMS-Condition-1: [M-18]⁺=632.20; Rt=2.58 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.66 (d, J=7.83 Hz, 2H), 7.56 (d, J=6.85Hz, 2H), 7.45-7.52 (m, 3H), 7.42 (d, J=6.85 Hz, 1H), 7.36 (d, J=7.83 Hz,2H), 7.31-7.35 (m, 1H), 7.22 (d, J=2.45 Hz, 1H), 7.03 (d, J=7.83 Hz,3H), 6.94-7.01 (m, 2H), 6.75 (d, J=7.83 Hz, 2H), 5.23 (s, 2H), 5.14-5.22(m, 2H), 4.21 (t, J=6.11 Hz, 2H), 3.87 (s, 3H), 2.83-2.89 (m, 2H), 2.43(s, 3H), 2.15 (s, 3H).

To4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 96-5 (309 mg, 0.476 mmol) in acetonitrile (3mL) was added DIPEA (0.49 mL, 2.856 mmol) and propyl amine (84.2 mg,1.428 mmol) and in a seal tube. The reaction mixture was further stirredat room temperature for 72 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure, was dilutedwith water and extracted with ethyl acetate (2×10 mL). The combinedorganic layer dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gelcolumn chromatography eluting with 0-2% methanol in DCM to afford 210 mg(82% yield) of compound 96-6 as brownish thick oil.

LCMS-Condition-1: [M+H]⁺=537.30; Rt=1.94 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.39-7.44 (m, 2H), 7.25-7.37 (m, 4H), 7.17(d, J=8.31 Hz, 1H), 7.06 (d, J=2.45 Hz, 1H), 6.96 (d, J=7.82 Hz, 2H),6.87 (d, J=2.45 Hz, 1H), 6.82 (dt, J=2.45, 8.31 Hz, 2H), 6.64 (d, J=8.31Hz, 2H), 5.08 (s, 2H), 5.03 (d, J=16.14 Hz, 2H), 3.73 (s, 3H), 2.62 (d,J=6.85 Hz, 2H), 2.52-2.57 (m, 2H), 2.00 (s, 3H), 1.27-1.36 (m, 2H), 1.17(s, 3H), 0.76 (t, J=7.58 Hz, 3H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(4-methoxy-2-methylphenyl)-1H-indol-1-yl)methyl)phenethyl)propan-1-amine96-6 (210 mg, 0.391 mmol) in ethyl acetate:methanol (1:1; 3 mL) wasadded 20% palladium hydroxide on carbon (100 mg) at room temperature.The reaction mixture was further stirred under hydrogen atmosphere for18 h. After completion of the reaction, the reaction mixture wasfiltered through pad of a Celite™ and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 35 mg (11% yield) of D-96 asoff white solid.

LCMS-Condition-1: [M+H]⁺=447.30; Rt=1.66 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.01 (br. s, 1H), 7.20-7.28 (m, 2H), 7.01(d, J=7.83 Hz, 2H), 6.92 (d, J=2.45 Hz, 1H), 6.86 (dd, J=2.45, 8.31 Hz,1H), 6.82 (d, J=1.96 Hz, 1H), 6.64-6.71 (m, 3H), 4.96-5.11 (m, 2H), 3.78(s, 3H), 2.55-2.66 (m, 4H), 2.43 (t, J=7.09 Hz, 2H), 2.06 (s, 3H),1.31-1.40 (m, 2H), 1.23 (s, 1H), 0.81 (t, J=7.34 Hz, 3H).

2-([1,1′-Biphenyl]-2-yl)-3-fluoro-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol(D-66)

To 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline 13-3 (1 g, 2.610 mmol) intoluene:ethanol (5:1, 12 mL) was added [1,1′-biphenyl]-2-ylboronic acid(672 mg, 3.393 mmol) and solution of Na₂CO₃ (830 mg, 27.830 mmol) inwater (2 mL) simultaneously at room temperature under argon atmosphereand degassed with argon for 30 min. To the resulting solution was addedPd(PPh₃)₄ (150 mg, 0.129 mmol) and degassing was continued for another10 min. The reaction mixture was then heated to 90° C. and stirred for18 h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was diluted with water and extracted with ethyl acetate(3×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-8% ethylacetate in n-hexane to afford 400 mg (40% yield) of compound 66-3 assticky solid.

LCMS-Condition-: [M+H]⁺=376.10; Rt=2.48 min

¹H NMR (400 MHz, DMSO-d₆) δ: 10.99 (br. s, 1H), 7.65 (d, J=7.34 Hz, 1H),7.40-7.51 (m, 4H), 7.34-7.40 (m, 4H), 7.31 (d, J=3.91 Hz, 4H), 7.22-7.26(m, 2H), 7.18 (d, J=8.31 Hz, 1H), 6.91 (d, J=1.96 Hz, 1H), 6.74 (dd,J=1.96, 8.80 Hz, 1H), 5.02 (s, 2H).

To 2-([1,1′-iphenyl]-2-yl)-5-(benzyloxy)-1H-indole 66-3 (400 mg, 1.065mmol) in dry Acetonitrile:DMSO (3:2, 5 mL) at −10° C. was addedselectfluor (380 mg, 1.072 mmol) under argon atmosphere. The reactionmixture was then stirred at room temperature for 2 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure, the residue was dissolved in ethyl acetate (100 mL) and washedwith water (40 mL) followed by brine (30 mL). The separated organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-4% ethyl acetate in n-hexane to afford 362mg (86% yield) of compound 66-4 as yellow thick oil which was forwardedfor the next reaction without further purification.

LCMS-Condition-1: [M-18]⁺=376.15; Rt=2.48 min

To 2-([1,1′-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indole 66-4 (362mg, 0.920 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 92 mg, 2.300 mmol) portion wise. The reaction mixturewas then stirred at 0° C. for 30 min. To the resulting solution wasadded (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (454 mg,1.378 mmol) and the reaction mixture was stirred at room temperature for4 h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×25 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-4% ethyl acetate in n-hexane to afford 360 mg (61% yield) ofcompound 66-5 as pale yellow thick oil.

LCMS-Condition-1: [M-18]⁺=624.35; Rt=2.90 min

¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.52 (m, 5H), 7.40 (ddd, J=2.22, 4.68,6.89 Hz, 3H), 7.18-7.22 (m, 5H), 7.14-7.18 (m, 2H), 6.96 (d, J=7.88 Hz,2H), 6.85-6.91 (m, 1H), 6.77-6.83 (m, 1H), 6.61 (d, J=8.37 Hz, 2H), 5.09(s, 2H), 4.51 (s, 2H), 3.80 (t, J=7.14 Hz, 2H), 2.83 (t, J=6.89 Hz, 2H),0.88 (s, 9H), 0.85 (s, 6H).

To2-([1,1′-biphenyl]-2-yl)-5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-1H-indole66-5 (360 mg, 0.560 mmol) in THE (4 mL) at 0° C. was added 1M solutionof tetrabutylammonium fluoride in THF (0.84 mL, 0.841 mmol) drop wise atroom temperature and stirred for 3 h. After completion of the reaction,the reaction mixture was quenched with ice cold water and extracted withethyl acetate (3×25 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 20-30% ethyl acetate in n-hexane to afford 168 mg (57% yield) ofcompound 66-6 as pale brown semi-solid.

LCMS-Condition-1: [M+H]⁺=528.15; Rt=2.35 min

¹H NMR (400 MHz, CDCl₃) δ: 7.49-7.51 (m, 1H), 7.43-7.49 (m, 4H),7.36-7.42 (m, 3H), 7.30-7.35 (m, 1H), 7.12-7.22 (m, 5H), 7.10 (d, J=2.42Hz, 1H), 6.97 (d, J=8.07 Hz, 2H), 6.88-6.92 (m, 1H), 6.76-6.83 (m, 1H),6.63 (d, J=8.07 Hz, 2H), 5.08 (s, 2H), 4.73 (s, 1H), 4.70 (s, 1H), 3.77(q, J=5.79 Hz, 2H), 2.73-2.78 (m, 2H).

To2-(4-((2-([1,1′-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethan-1-ol66-6 (160 mg, 0.303 mmol) in CH₂Cl₂ (3 mL) at 0° C. was addedtriethylamine (0.17 mL, 1.255 mmol) followed by tosyl chloride (92 mg,0.480 mmol). The reaction mixture was stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was dilutedwater and extracted with CH₂Cl₂ (3×30 mL). The combined organic layerdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to afford 178 mg (83% yield) of the title compound 66-7 as paleyellow thick oil.

LCMS-Condition-1: [M+H]⁺=682.20; Rt=2.54 min

¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J=8.28 Hz, 2H), 7.37-7.53 (m, 8H),7.28-7.35 (m, 2H), 7.14-7.23 (m, 7H), 6.78-6.88 (m, 4H), 6.54-6.58 (m,2H), 5.08 (s, 2H), 4.65-4.70 (m, 2H), 4.06-4.14 (m, 2H), 2.81-2.86 (m,2H), 2.39 (s, 2H), 2.38 (s, 3H).

To4-((2-([1,1′-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 66-7 (175 mg, 0.256 mmol) in acetonitrile (3mL) was added DIPEA (0.27 mL, 1.539 mmol) and propyl amine (0.06 mL,0.761 mmol). The reaction mixture was stirred at room temperature for 4days in a sealed tube. After completion of the reaction, the reactionmixture was concentrated under reduced pressure, washed with ethylacetate (2×10 mL). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-5% methanol in DCM to afford 131 mg (91% yield) of compound 66-8 aspale yellow solid.

LCMS-Condition-1: [M+H]⁺=569.30; Rt=1.92 min

¹H NMR (400 MHz, CDCl₃) δ: 7.72 (d, J=8.31 Hz, 1H), 7.31-7.50 (m, 10H),7.12-7.20 (m, 6H), 6.90 (d, J=8.31 Hz, 2H), 6.57 (d, J=8.31 Hz, 2H),5.07 (s, 2H), 4.67 (d, J=8.31 Hz, 2H), 2.97 (s, 3H), 2.76-2.82 (m, 2H),2.31 (s, 2H), 1.72 (qd, J=7.50, 15.16 Hz, 2H), 0.85-0.92 (m, 3H).

ToN-(4-((2-([1,1′-biphenyl]-2-yl)-5-(benzyloxy)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)propan-1-amine66-8 (120 mg, 0.211 mmol) in ethyl acetate:methanol (2:1, 3 mL) wasadded 20% palladium hydroxide on carbon (40 mg, 20% w/w) at roomtemperature. The reaction mixture was then stirred under hydrogenatmosphere at room temperature for 3 h. After completion of thereaction, the reaction mixture was filtered through pad of a Celite™ andwashed with ethyl acetate. The filtrate was concentrated under reducedpressure and the crude compound was purified by preparative HPLC toafford 36 mg (36% yield) of D-66 as pale brown solid.

LCMS-Condition-1: [M+H]⁺=479.30; Rt=1.53 min

¹H NMR (400 MHz, CDCl₃) δ: 7.49 (d, J=3.42 Hz, 2H), 7.41-7.46 (m, 1H),7.36-7.41 (m, 1H), 7.17 (d, J=5.87 Hz, 3H), 7.14 (br. s, 2H), 6.88-6.97(m, 3H), 6.80 (d, J=7.34 Hz, 1H), 6.56-6.65 (m, 3H), 4.68 (q, J=16.47Hz, 2H), 2.83-2.90 (m, 2H), 2.71-2.78 (m, 2H), 2.64 (t, J=7.34 Hz, 2H),1.52 (qd, J=7.34, 14.67 Hz, 2H), 0.87 (t, J=7.34 Hz, 3H)

1-(4-(2-(Ethylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol(D-29)

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (225 mg, 0.363 mmol) in acetonitrile (5mL) was added DIPEA (0.63 mL, 3.364 mmol) and 2M solution of ethyl aminein THE (1.8 mL, 164 mg, 3.634 mmol) and in a sealed tube. The reactionmixture was further stirred at room temperature for 72 h. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure, and diluted with ethyl acetate. Organic layer waswashed with water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 175 mg (97% yield) ofcompound 29-1 as off white solid.

LCMS-Condition 01: [M+H]⁺=493.29; Rt=1.49 min

¹H NMR (400 MHz, CDCl₃) δ: 9.43 (s, 1H), 7.70-7.75 (m, 1H), 7.48 (d,J=7.34 Hz, 1H), 7.39 (t, J=7.09 Hz, 2H), 7.28-7.35 (m, 2H), 7.13-7.25(m, 3H), 7.05-7.11 (m, 1H), 6.99 (d, J=7.83 Hz, 2H), 6.91 (dd, J=2.45,8.80 Hz, 1H), 6.69-6.79 (m, 2H), 5.09-5.14 (m, 2H), 4.92-5.06 (m, 2H),2.98-3.14 (m, 4H), 2.15-2.21 (m, 5H), 1.41 (t, J=7.34 Hz, 3H.

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)-N-ethylethan-1-amine29-1 (175 mg, 0.366 mmol) in ethyl acetate:methanol (4:1; 4 mL) wasadded 20% palladium hydroxide on carbon (35 mg, 20% w/w) at roomtemperature. The reaction mixture was further stirred under hydrogenatmosphere for 3 h. After completion of the reaction, the reactionmixture was filtered through a pad of Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 15 mg (11%yield) of D-29 as white solid.

LCMS-Condition 01: [M+H]⁺=403.24; Rt=1.49 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.27-7.41 (m, 5H), 7.00 (d,J=7.83 Hz, 2H), 6.84 (d, J=1.96 Hz, 1H), 6.70 (dd, J=2.45, 8.80 Hz, 1H),6.66 (d, J=7.83 Hz, 2H), 5.00-5.13 (m, 2H), 2.54-2.68 (m, 4H), 2.46-2.49(m, 2H), 2.08 (s, 3H), 1.22-1.26 (m, 1H), 0.95 (t, J=7.09 Hz, 3H).

1-(4-(2-((Cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol(D-39)

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (200 mg, 0.323 mmol) in acetonitrile (4mL) was added cyclopropylmethanamine (229 mg, 3.230 mmol) and DIPEA (416mg, mL, 3.230 mmol) in a sealed tube. The reaction mixture was thenstirred at room temperature for 72 h. After completion of the reaction,the reaction mixture was concentrated under reduced pressure, dilutedwith ethyl acetate. Organic layer was washed with water (20 mL), brine(20 mL); dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford 140 mg (84% yield) of compound 39-1 ascolourless thick oil.

LCMS-Condition 01: [M+H]⁺=519.30; Rt=1.89 min

To1-(4-(2-((cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol39-1 (140 mg, 0.270 mmol) in ethyl acetate:methanol (1:1; 3 mL) wasadded 20% palladium hydroxide on carbon (45 mg) at room temperatureunder nitrogen atmosphere. The reaction mixture was then stirred underhydrogen atmosphere for 2 h. After completion of the reaction, thereaction mixture was filtered through a pad of Celite™ and washed with amixture of methanol and ethyl acetate. The filtrate was concentratedunder reduced pressure and the crude compound was purified bypreparative HPLC to afford 22 mg (19% yield) of D-39 as off white solid.

LCMS-Condition 01: [M+H]⁺=429.55; Rt=1.55 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.99-9.01 (m, 1H), 7.30-7.37 (m, 2H),7.24-7.29 (m, 3H), 6.97 (d, J=8.31 Hz, 2H), 6.80 (d, J=1.96 Hz, 1H),6.67 (dd, J=1.96, 8.80 Hz, 1H), 6.63 (d, J=8.31 Hz, 2H), 5.03 (d, J=8.31Hz, 2H), 2.60-2.65 (m, 2H), 2.51-2.57 (m, 2H), 2.40-2.43 (m, 1H), 2.31(d, J=6.36 Hz, 2H), 2.04 (s, 3H), 1.20 (s, 1H), 0.73-0.82 (m, 2H),0.29-0.35 (m, 2H).

1-(4-(2-(Cyclobutylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol(D-46)

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (200 mg, 0.323 mmol) in acetonitrile (4mL) was added cyclobutyl amine (232 mg, 3.230 mmol) and DIPEA (0.56 mL,3.230 mmol) in a sealed tube. The reaction mixture was then stirred atroom temperature for 72 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure, and dilutedwith ethyl acetate. Organic layer was washed with water (20 mL), brine(20 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford 150 mg (89% yield) of compound 46-1 ascolourless oil which was used in the next reaction without furtherpurification.

LCMS-Condition 01: [M+H]⁺=519.35; Rt=1.95 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.47 (d, J=7.83 Hz, 4H), 7.37-7.43 (m, 4H),7.29-7.35 (m, 3H), 7.11 (d, J=8.31 Hz, 2H), 7.04 (d, J=7.83 Hz, 2H),6.91 (dd, J=1.96, 8.80 Hz, 1H), 6.71 (d, J=7.83 Hz, 1H), 5.15 (s, 2H),5.11 (s, 2H), 2.90 (t, J=6.60 Hz, 2H), 2.67 (dt, J=7.34, 19.07 Hz, 5H),2.28 (s, 3H), 2.09-2.13 (m, 2H), 0.9-1.2 (m, 2H).

To1-(4-(2-(cyclobutylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ylbenzoate 46-1 (150 mg, 0.289 mmol) in ethyl acetate:methanol (1:1; 3 mL)was added 20% palladium hydroxide on carbon (49 mg, 30% w/w) at roomtemperature. The reaction mixture was stirred under hydrogen atmospherefor 2 h. After completion of the reaction, the reaction mixture wasfiltered through a pad of Celite™ and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 50 mg (39% yield) of D-46 asbrown solid.

LCMS-Condition 01: [M+H]⁺=429.25; Rt=1.54 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.27-7.41 (m, 5H), 7.00 (d,J=7.83 Hz, 2H), 6.84 (d, J=1.96 Hz, 1H), 6.71 (d, J=1.96 Hz, 1H),6.65-6.70 (m, 2H), 4.99-5.13 (m, 2H), 3.14-3.20 (m, 1H), 2.54-2.60 (m,4H), 2.09 (s, 3H), 2.01-2.07 (m, 2H), 1.51-1.69 (m, 4H).

3-Fluoro-1-(4-(2-(propylamino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-01(D-67)

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (250 mg, 0.4038 mmol) in acetonitrile (4mL) was added DIPEA (0.7 mL, 4.040 mmol) and propyl amine (238 mg, 4.040mmol) in a sealed tube. The reaction mixture was then stirred at roomtemperature for 72 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure, and diluted with ethylacetate. Organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 145 mg (70% yield) ofcompound 67-1 as colorless thick oil. LCMS: [M+H]⁺=507.65; Rt=1.77 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.47 (d, J=7.34 Hz, 3H), 7.30-7.43 (m, 7H),7.15 (d, J=1.96 Hz, 1H), 7.11 (d, J=7.82 Hz, 1H), 7.06 (d, J=7.82 Hz,2H), 6.91 (dd, J=2.45, 9.29 Hz, 1H), 6.73 (d, J=8.31 Hz, 1H), 5.15 (s,2H), 5.09-5.13 (m, 2H), 2.90-2.98 (m, 2H), 2.75 (t, J=7.58 Hz, 4H), 2.28(s, 1H), 2.11-2.13 (m, 3H), 1.47-1.58 (m, 2H), 0.87 (t, J=7.34 Hz, 3H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)propan-1-amine67-1 (140 mg, 0.276 mmol) in ethyl acetate:methanol (1:1; 4 mL) wasadded 20% palladium hydroxide on carbon (48.4 mg, 30% w/w) at roomtemperature. The reaction mixture was stirred under hydrogen atmospherefor 2 h. After completion of the reaction, the reaction mixture wasfiltered through a pad of Celite™ and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 35 mg (30% yield) of D-67 asoff white solid.

LCMS: [M+H]⁺=417.45; Rt=1.43 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (br. s, 1H), 7.28-7.41 (m, 5H), 7.00(d, J=8.31 Hz, 2H), 6.84 (d, J=1.96 Hz, 1H), 6.70 (dd, J=2.45, 8.80 Hz,1H), 6.66 (d, J=7.83 Hz, 2H), 5.00-5.12 (m, 2H), 2.53-2.64 (m, 4H), 2.42(t, J=7.09 Hz, 2H), 2.08 (s, 3H), 1.29-1.40 (m, 2H), 1.23 (s, 1H), 0.81(t, J=7.34 Hz, 3H).

1-(4-(2-(Butylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-01(D-68)

To 4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (250 mg, 0.4038 mmol) in acetonitrile (4mL) was added butyl amine (295 mg, 4.040 mmol) and DIPEA (0.7 mL, 4.040mmol) in a sealed tube. The reaction mixture was stirred at roomtemperature for 72 h. After completion of the reaction, the reactionmixture was concentrated under reduced pressure, and diluted with ethylacetate. Organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 240 mg (crude) of compound68-1 as off white solid.

LCMS: [M+H]⁺=521.75; Rt=1.80 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.47 (d, J=7.82 Hz, 4H), 7.37-7.43 (m, 3H),7.25-7.36 (m, 4H), 7.11 (d, J=7.83 Hz, 2H), 7.05 (d, J=7.82 Hz, 1H),6.91 (dd, J=2.20, 9.05 Hz, 1H), 6.73 (d, J=7.83 Hz, 1H), 5.15 (s, 2H),2.90-2.98 (m, 2H), 2.70-2.80 (m, 4H), 2.28 (s, 3H), 2.10-2.14 (m, 2H),1.45-1.49 (m, 2H), 1.28 (dq, J=6.60, 14.43 Hz, 3H), 0.83-0.90 (m, 3H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)butan-1-amine68-1 (240 mg, 0.4615 mmol) in ethyl acetate:methanol (1:1; 4 mL) wasadded 20% palladium hydroxide on carbon (77.5 mg, 30% w/w) at roomtemperature. The reaction mixture was further stirred under hydrogenatmosphere for 18 h. After completion of the reaction, the reactionmixture was filtered through a pad of Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 50 mg (25%yield) of D-68 as light brown solid.

LCMS: [M+H]⁺=431.20; Rt=1.59 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02-9.15 (m, 1H), 7.27-7.41 (m, 5H), 6.99(d, J=8.31 Hz, 2H), 6.84 (d, J=2.45 Hz, 1H), 6.70 (dd, J=1.96, 8.80 Hz,1H), 6.66 (d, J=7.82 Hz, 2H), 5.00-5.12 (m, 2H), 2.58 (qd, J=5.79, 11.49Hz, 4H), 2.44 (t, J=6.85 Hz, 2H), 2.08 (s, 3H), 1.20-1.36 (m, 5H),0.80-0.86 (m, 3H).

3-Fluoro-1-(4-(2-((3-fluoropropyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-ol(D-69)

To a solution of4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 28-5 (500 mg, 0.807 mmol) in DMF (10 mL) wasadded potassium phthalimide (164 mg, 0.886 mmol) at room temperature.The reaction mixture was then heated to 80° C. for 3 h. After completionof the reaction, the reaction mixture was cooled to room temperature,diluted with ethyl acetate (100 mL) washed with water (30 mL), brine (30mL). Organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford 510 mg (crude) of compound69-6 as yellowish solid which was forwarded for the next reactionwithout further purification.

LCMS-Condition-1: [M+H]⁺=595.30; Rt=2.66 min

To a solution of2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)isoindoline-1,3-dione69-6 (550 mg, 0.925 mmol) in ethanol (8 mL) was added hydrazine hydrate(55.6 mg, 1.018 mmol) at room temperature. The reaction mixture was thenheated at 80° C. for 2 h. After completion of the reaction (monitored byTLC), the reaction mixture was concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-3% methanol in DCM to afford 265 mg (62% yield) of compound 69-7as white solid.

LCMS-Condition-1: [M+H]⁺=465.25; Rt=1.98 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.52-7.57 (m, 2H), 7.43-7.51 (m, 3H),7.37-7.43 (m, 3H), 7.32-7.36 (m, 1H), 7.20-7.25 (m, 1H), 7.07-7.12 (m,2H), 6.99 (dd, J=2.45, 8.80 Hz, 1H), 6.90 (dd, J=2.45, 8.80 Hz, 1H),6.80 (d, J=7.83 Hz, 1H), 6.76 (d, J=8.31 Hz, 1H), 5.14 (s, 2H), 5.10 (s,2H), 2.75-2.77 (m, 2H), 2.49-2.61 (m, 2H), 2.09 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-amine69-7 (260 mg, 0.560 mmol) in acetonitrile (4 mL) was added potassiumcarbonate (77.3 mg, 0.560 mmol) and 1-iodo-3-fluoro propane (105 mg,0.560 mmol) at room temperature and stirred for 24 h. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-2% methanol in DCM to afford 140 mg (48%yield) of compound 69-8 as colorless thick oil.

LCMS-Condition-1: [M+H]⁺=525.25; Rt=1.76 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.50 (m, 2H), 7.32-7.44 (m, 6H),7.12-7.18 (m, 1H), 7.00-7.05 (m, 2H), 6.92 (dd, J=2.20, 9.05 Hz, 1H),6.83 (dd, J=2.45, 8.80 Hz, 1H), 6.72 (d, J=7.83 Hz, 1H), 6.68 (d, J=7.83Hz, 1H), 6.39 (s, 1H), 5.15 (s, 1H), 5.11 (s, 1H), 4.52 (t, J=5.87 Hz,1H), 4.40 (t, J=6.11 Hz, 1H), 2.62 (d, J=6.85 Hz, 6H), 2.07-2.12 (m,3H), 1.75 (qd, J=6.32, 19.69 Hz, 2H), 1.22-1.26 (m, 3H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)-3-fluoropropan-1-amine69-8 (130 mg, 0.248 mmol) in ethyl acetate:methanol (2:1, 3 mL) wasadded 20% palladium hydroxide on carbon (71.5 mg, 30% w/w) at roomtemperature. The reaction mixture was then stirred under hydrogenatmosphere for 2 h. After completion of the reaction (monitored by TLCand LCMS), the reaction mixture was filtered through a pad of Celite™and washed with methanol and ethyl acetate. The filtrate wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 20 mg (19% yield) of D-69 as light yellowsolid.

LCMS-Condition-1: [M+H]⁺=435.20; Rt=1.43 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.27-7.42 (m, 5H), 7.00 (d,J=7.83 Hz, 2H), 6.84 (d, J=1.47 Hz, 1H), 6.69-6.72 (m, 1H), 6.66 (d,J=7.83 Hz, 2H), 4.99-5.12 (m, 2H), 4.50 (t, J=5.87 Hz, 1H), 4.38 (t,J=5.87 Hz, 1H), 2.53-2.65 (m, 8H), 2.06-2.11 (m, 3H), 1.65-1.78 (m, 3H).

3-Fluoro-1-(4-(2-((2-fluoroethyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-ol(D-70)

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-amine69-7 (150 mg, 0.323 mmol) in THE (8 mL) was added triethylamine (0.13mL, 0.969 mmol) and 1-fluoro-2-iodoethane (56.2 mg, 0.323 mmol) at roomtemperature in a seal tube. The reaction mixture was then heated to 80°C. and stirred for 18 h. After completion of the reaction (monitored byTLC), the reaction mixture was concentrated under reduced pressure andthe crude residue was purified by silica gel column chromatographyeluting with 0-2% methanol in DCM to afford 91 mg (55% yield) ofcompound 70-8 as colourless thick oil.

LCMS-Condition-1: [M+H]⁺=511.63; Rt=1.71 min

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenethyl)-2-fluoroethan-1-amine70-8 (90 mg, 0.176 mmol) in ethyl acetate:methanol (2:1, 3 mL) was added20% palladium hydroxide on carbon (29.6 mg, 30% w/w) at roomtemperature. The reaction mixture was then stirred under hydrogenatmosphere for 12 h. After completion of the reaction (monitored by TLCand LCMS), the reaction mixture was filtered through a pad of Celite™and washed with methanol and ethyl acetate. The filtrate wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 15 mg (20% yield) of D-70 as light brownsolid.

LCMS-Condition-1: [M+H]⁺=421.30; Rt=1.38 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.27-7.41 (m, 5H), 7.01 (d,J=7.83 Hz, 2H), 6.84 (d, J=1.96 Hz, 1H), 6.70 (dd, J=2.45, 8.80 Hz, 1H),6.67 (d, J=7.83 Hz, 2H), 5.00-5.14 (m, 2H), 4.49 (t, J=4.89 Hz, 1H),4.37 (t, J=4.89 Hz, 1H), 2.83 (t, J=4.89 Hz, 1H), 2.76 (t, J=4.89 Hz,1H), 2.66-2.73 (m, 2H), 2.55-2.63 (m, 2H), 2.08 (s, 3H).

1-(4-(2-(Cyclopropylamino)propyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol(D-32)

To 5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indole 28-2 (600 mg, 1.812mmol) in DMF (3 mL) at 0° C. was added sodium hydride (60% dispersion inoil, 27.2 mg, 1.132 mmol) portion wise and stirred at the sametemperature for 30 min. To the resulting solution was added2-(4-(bromomethyl)phenyl)acetic acid 1 (456 mg, 1.994 mmol) in DMF (1mL) and stirred at room temperature for 18 h. After completion of thereaction, the reaction mixture was quenched with ice cold water andacidified with dilute hydrochloride solution up to pH=2. The solidprecipitated was filtered and washed to afford 820 mg (94% yield) ofcompound 32-2 as yellow solid.

LCMS-Condition 01: [M-18]⁺=462.50; Rt=2.29 min

¹H NMR (400 MHz, DMSO-d₆) δ: 12.24 (br. s, 1H), 7.45-7.49 (m, 2H),7.23-7.42 (m, 10H), 7.14 (d, J=1.96 Hz, 1H), 7.05 (d, J=7.82 Hz, 2H),6.91 (dd, J=2.20, 9.05 Hz, 1H), 6.67-6.72 (m, 2H), 5.14 (s, 2H), 3.44(s, 2H), 2.10 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)aceticacid 32-2 (500 mg, 1.043 mmol) in DMF (2 mL) was added HATU (475 mg,1.250 mmol), DIPEA (0.9 mL, 5.209 mmol) and N-methyl N-methoxylamine(191 mg, 31.27 mmol) at room temperature and stirred for 18 h. Aftercompletion of the reaction, the reaction mixture was quenched with icecold water and extracted with ethyl acetate (2×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-20% ethyl acetate in n-hexaneto afford 350 mg (64% yield) of compound 32-3 as yellow oil.

LCMS-Condition 01: [M+H]⁺=523.60; Rt=2.36 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.50 (m, 2H), 7.24-7.43 (m, 8H), 7.14(d, J=2.49 Hz, 1H), 7.03 (d, J=7.98 Hz, 2H), 6.91 (dd, J=2.49, 8.98 Hz,1H), 6.70 (d, J=8.48 Hz, 2H), 5.15 (s, 2H), 5.09-5.12 (m, 2H), 3.60-3.62(m, 2H), 3.60 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)-N-methoxy-N-methylacetamide32-3 (300 mg, 0.574 mmol) in THF (5 mL) at 0° C. was added 3M methylmagnesium bromide solution in diethyl ether (0.38 mL, 1.140 mmol). Thereaction mixture was further stirred at room temperature for 5 h. Aftercompletion of the reaction, the reaction mixture was quenched with icecold water and extracted with ethyl acetate (2×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-5% methanol in DCM to afford250 mg (91% yield) of compound 32-4 as colourless oil.

LCMS-Condition 01: [M-18]⁺=460.55; Rt=2.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46-7.50 (m, 2H), 7.27-7.45 (m, 8H), 7.14(d, J=2.45 Hz, 1H), 6.98 (d, J=8.31 Hz, 2H), 6.92 (dd, J=2.45, 9.29 Hz,1H), 6.69 (d, J=8.31 Hz, 2H), 5.11-5.15 (m, 4H), 3.64 (s, 2H), 2.10 (s,3H), 2.05 (s, 3H).

To1-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)propan-2-one32-4 (250 mg, 0.524 mmol) in EDC (6 mL) at 0° C. was added sodiumtriacetoxy borohydride (555 mg, 2.617 mmol) portion wise, followed bycyclopropanamine (89 mg, 1.558 mmol). The reaction mixture was stirredat room temperature for 18 h. After completion of the reaction, thereaction mixture was quenched with ice cold water and extracted withethyl acetate (2×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 158 mg (58% yield) ofcompound 32-5 as colourless oil.

LCMS-Condition-1: [M+H]⁺=519.60; Rt=1.78 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.80-7.87 (m, 1H), 7.42-7.47 (m, 3H),7.25-7.40 (m, 7H), 7.08-7.14 (m, 1H), 6.93 (d, J=7.83 Hz, 2H), 6.87-6.91(m, 1H), 6.61 (d, J=7.83 Hz, 2H), 5.12 (s, 2H), 5.08 (d, J=4.89 Hz, 2H),2.74-2.85 (m, 1H), 2.61-2.70 (m, 2H), 2.50-2.58 (m, 1H), 2.23-2.31 (m,2H), 2.00 (s, 3H), 0.82 (d, J=6.36 Hz, 3H), 0.50-0.57 (m, 2H).

ToN-(1-(4-((5-(benzyloxy)-3-fluoro-2-(o-tolyl)-1H-indol-1-yl)methyl)phenyl)propan-2-yl)cyclopropanamine32-5 (150 mg, 0.289 mmol) in ethyl acetate:methanol (1:1 mL) was added20% palladium hydroxide on carbon (50 mg, 50% moisture on carbon) atroom temperature. The reaction mixture was then stirred under hydrogenatmosphere for 18 h. After completion of the reaction, the reactionmixture was filtered through a pad of Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 40 mg (32%yield) of D-32 as colourless oil.

LCMS-Condition-1: [M+H]⁺=429.50; Rt=1.42 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.28-7.40 (m, 6H), 6.95 (d,J=7.82 Hz, 2H), 6.84 (d, J=1.96 Hz, 1H), 6.71 (dd, J=2.45, 8.80 Hz, 1H),6.64 (d, J=8.31 Hz, 2H), 5.07 (s, 2H), 2.75-2.83 (m, 1H), 2.67 (ddd,J=2.69, 5.75, 13.08 Hz, 2H), 2.53-2.60 (m, 1H), 2.25-2.34 (m, 2H), 2.03(s, 3H), 0.85 (d, J=6.36 Hz, 3H), 0.50-0.57 (m, 2H).1-(4-(2-((Cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol(D-40)

To 5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole 40-1(1 g, 2.597 mmol) in DMF (10 mL) at 0° C. was added 60% dispersionsodium hydride in oil (370 mg, 7.791 mmol) portionwise. The reactionmixture was further stirred at 0° C. for 30 min. To the resultingsolution was added (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane(1.1 g, 3.376 mmol). The reaction mixture was stirred at roomtemperature for 18 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (thrice). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-10% ethyl acetate in n-hexane to afford 747 mg (45% yield) ofcompound 40-2 as brown thick oil.

LCMS-Condition 01: [M+H]⁺=634.25; Rt=2.83 min

¹H NMR (400 MHz, CDCl₃) δ: 7.82 (d, J=7.34 Hz, 1H), 7.52-7.60 (m, 1H),7.49 (d, J=7.34 Hz, 2H), 7.41 (t, J=7.34 Hz, 1H), 7.33 (dd, J=7.34,11.74 Hz, 2H), 7.19 (d, J=1.96 Hz, 1H), 7.09-7.12 (m, 3H), 7.03-7.08 (m,2H), 6.92 (dd, J=2.45, 9.29 Hz, 1H), 6.81 (d, J=7.82 Hz, 2H), 5.14 (br.s, 1H), 5.13 (s, 1H), 5.10 (br. s, 1H), 4.79 (d, J=17.12 Hz, 1H),3.75-3.80 (m, 2H), 2.77-2.81 (m, 2H), 0.89 (s, 6H), 0.88 (s, 3H), 0.01(s, 3H), 0.00 (s, 3H).

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indole40-2 (800 mg, 1.263 mmol) in THE (8 mL) at 0° C. was added 2M solutionof TBAF in THF (495 mg, 1.896 mmol). The reaction mixture was furtherstirred at room temperature for 2 h. After completion of the reaction,the reaction mixture was quenched with ice cold water and extracted withethyl acetate (thrice). The combined organic layer dried was washed withwater (20 mL) and brine (20 mL) dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The resulting crude compoundwas purified by silica gel column chromatography eluting with 0-50%ethyl acetate in n-hexane to afford 550 mg (84% yield) of compound 40-3as thick colorless syrup.

LCMS-Condition 01: [M+H]⁺=520.18; Rt=2.36 min

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (d, J=7.34 Hz, 1H), 7.51-7.59 (m, 2H),7.48 (d, J=7.34 Hz, 2H), 7.40 (t, J=7.34 Hz, 2H), 7.33 (dd, J=7.58,10.03 Hz, 2H), 7.18 (d, J=1.96 Hz, 1H), 7.05-7.09 (m, 3H), 6.93 (dd,J=2.45, 8.80 Hz, 1H), 6.83 (d, J=8.31 Hz, 2H), 5.12 (s, 2H), 5.09 (s,1H), 4.81 (d, J=16.63 Hz, 1H), 4.09-4.15 (m, 1H), 3.83-3.88 (m, 2H),2.83-2.87 (m, 2H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)ethan-1-ol40-3 (560 mg, 1.117 mmol) in CH₂Cl₂ (10 mL) at 0° C. was addedtriethylamine (0.46 mL, 1.564 mmol) followed by Tosyl chloride (299 mg,1.564 mmol). The reaction mixture was stirred at room temperature for 3h. After completion of the reaction, the reaction mixture was dilutedwith CH₂Cl₂ (50 mL) and washed with water (20 mL) and brine (10 mL). Thecombined organic layer dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude compound waspurified by silica gel column chromatography eluting with 0-25% ethylacetate in n-hexane to afford 630 mg (86% yield) of compound 40-4 asthick colorless syrup.

LCMS-Condition 01: [M+H]⁺=674.05; Rt=2.46 min

¹H NMR (400 MHz, CDCl₃) δ: 7.81 (d, J=7.34 Hz, 1H), 7.69 (dd, J=8.31,10.76 Hz, 2H), 7.46-7.59 (m, 3H), 7.40 (t, J=7.58 Hz, 1H), 7.34 (d,J=6.85 Hz, 1H), 7.28 (d, J=8.80 Hz, 2H), 7.25 (br. s, 1H), 7.21-7.24 (m,2H), 7.18 (d, J=2.45 Hz, 1H), 7.01-7.09 (m, 3H), 6.94-6.98 (m, 2H), 6.77(d, J=7.83 Hz, 1H), 5.12 (s, 2H), 4.12-4.22 (m, 2H), 2.86-2.96 (m, 2H),2.85 (s, 1H), 2.43 (s, 2H), 2.40 (s, 1H), 2.00 (s, 1H).

To4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 40-4 (225 mg, 0.334 mmol) in acetonitrile (4mL) was added Cyclopropylmethylamine (0.200 g, 3.324 mmol) and DIPEA(0.57 mL, 3.380 mmol) in a seal tube. The reaction mixture was furtherstirred at room temperature for 72 h. After completion of the reaction,the reaction mixture was concentrated under reduced pressure, washedwith ethyl acetate (2×10 mL). The combined organic layer dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford 210 mg (crude) of compound 40-5 as colorless residue.

LCMS-Condition 01: [M+H]⁺=573.20; Rt=1.79 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.91-7.95 (m, 1H), 7.73-7.77 (m, 1H),7.46-7.49 (m, 3H), 7.40 (t, J=7.34 Hz, 1H), 7.16-7.35 (m, 4H), 7.07-7.15(m, 4H), 6.93 (dd, J=2.45, 8.80 Hz, 1H), 6.82 (d, J=7.83 Hz, 1H), 5.23(d, J=16.63 Hz, 1H), 5.16 (s, 1H), 4.87 (d, J=17.12 Hz, 1H), 3.02 (dd,J=9.29, 19.07 Hz, 2H), 2.79-2.86 (m, 2H), 2.72-2.78 (m, 2H), 2.29 (s,2H), 0.94-1.01 (m, 1H), 0.54 (dt, J=1.96, 6.11 Hz, 2H), 0.29 (dd,J=4.89, 11.25 Hz, 2H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)-N-(cyclopropylmethyl)ethan-1-amine40-5 (210 mg, 0.367 mmol) in ethyl acetate:methanol (2:2 mL) was added20% palladium hydroxide on carbon (51 mg) at room temperature. Thereaction mixture was further stirred under hydrogen atmosphere for 2 h.After completion of the reaction, the reaction mixture was filteredthrough pad of a Celite™ and washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 22 mg (13% yield) of D-40 as off whitesolid.

LCMS-Condition-1: [M+H]⁺=483.15; Rt=1.46 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.25 (s, 1H), 7.83-7.87 (m, 1H), 7.65-7.69(m, 2H), 7.41-7.46 (m, 1H), 7.13 (d, J=8.80 Hz, 1H), 7.00 (d, J=8.31 Hz,2H), 6.79 (d, J=1.96 Hz, 1H), 6.72 (d, J=7.83 Hz, 2H), 6.66 (dd, J=1.96,8.80 Hz, 1H), 5.11 (d, J=16.63 Hz, 1H), 4.74 (d, J=16.63 Hz, 1H),2.79-2.86 (m, 2H), 2.64-2.71 (m, 2H), 2.54 (d, J=6.85 Hz, 2H), 0.81-0.91(m, 1H), 0.37-0.43 (m, 2H), 0.10-0.16 (m, 2H).1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol(D-33)

To4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate D-40-4 (0.225 g, 0.334 mmol) in acetonitrile (4mL) was added cyclopropyl amine (0.200 g, 3.324 mmol) and DIPEA (0.57mL, 3.380 mmol) in a sealed tube. The reaction mixture was stirred atroom temperature for 72 h. After completion of the reaction, thereaction mixture was concentrated under reduced pressure and extractedwith ethyl acetate (3×). The combined organic layer washed with waterand Brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford 220 mg (crude) of compound 33-3 as colourlessoil.

LCMS-Condition 01: [M+H]⁺=559.20; Rt=1.75 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.91-7.95 (m, 1H), 7.73-7.77 (m, 1H),7.50-7.54 (m, 1H), 7.45-7.50 (m, 4H), 7.40 (t, J=7.34 Hz, 2H), 7.29-7.36(m, 2H), 7.10 (dd, J=3.67, 8.07 Hz, 3H), 6.93 (dd, J=2.20, 9.05 Hz, 1H),6.81 (d, J=7.82 Hz, 1H), 5.21 (d, J=16.8 Hz, 1H), 5.15 (s, 2H), 4.48 (d,J=16.8 Hz, 1H), 3.05-3.11 (m, 2H), 2.75-2.80 (m, 2H), 2.28 (s, 2H), 1.25(d, J=6.85 Hz, 4H).

ToN-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine33-3 (0.230 g, 0.413) in ethyl acetate:methanol (2:2 mL) was added 20%palladium hydroxide on carbon (70 mg) at room temperature. The reactionmixture was then stirred under hydrogen atmosphere for 2 h. Aftercompletion of the reaction, the reaction mixture was filtered through apad of Celite™ and washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 18 mg (10% yield) of D-33 as off whitesolid.

LCMS-Condition-1: [M+H]⁺=469.10; Rt=1.45 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 8.16 (s, 1H), 7.88-7.93 (m,1H), 7.70-7.76 (m, 2H), 7.47-7.50 (m, 1H), 7.21 (dd, J=1.83, 8.93 Hz,1H), 7.04 (d, J=8.07 Hz, 2H), 6.85 (d, J=2.08 Hz, 1H), 6.75 (d, J=7.95Hz, 2H), 6.72 (dd, J=2.32, 8.93 Hz, 1H), 5.16 (d, J=16.75 Hz, 1H), 4.80(d, J=16.75 Hz, 1H), 2.73-2.78 (m, 2H), 2.59-2.65 (m, 2H), 2.10-2.14 (m,1H), 0.33-0.38 (m, 2H), 0.19-0.24 (m, 2H).1-(4-(2-(Ethylamino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol(D-34)

To4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 33-2 (0.225 g, 0.334 mmol) in acetonitrile (5mL) was added 2M ethyl amine in THF (150 mg, 1.66 mL, 3.324 mmol) andDIPEA (0.57 mL, 3.380 mmol) in a sealed tube. The reaction mixture wasthen stirred at room temperature for 72 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressureand extracted with ethyl acetate (3×). The combined organic layer washedwith water (20 mL), brine (20 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford 195 mg(crude) of compound 34-1 as colourless thick oil.

LCMS-Condition 01: [M+H]⁺=547.26; Rt=1.77 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.24-8.33 (m, 1H), 7.90-7.96 (m, 1H), 7.75(d, J=3.91 Hz, 1H), 7.52 (br. s, 1H), 7.47 (d, J=6.85 Hz, 3H), 7.37-7.43(m, 2H), 7.26-7.37 (m, 2H), 7.10 (d, J=7.83 Hz, 3H), 6.93 (d, J=8.80 Hz,1H), 6.83 (d, J=7.83 Hz, 2H), 5.24 (d, J=16.63 Hz, 1H), 5.15 (br. s,2H), 4.81-4.90 (m, 1H), 3.02-3.10 (m, 2H), 2.91-3.00 (m, 2H), 2.75-2.83(m, 2H), 1.12-1.17 (m, 3H).

To2-(4-((5-(benzyloxy)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-1-yl)methyl)phenyl)-N-ethylethan-1-amine34-1 (0.195 g, 0.357 mmol) in ethyl acetate:methanol (1:1, 4 mL) wasadded 20% palladium hydroxide on carbon (60 mg) at room temperature. Thereaction mixture was stirred under hydrogen atmosphere for 18 h. Aftercompletion of the reaction, the reaction mixture was filtered through apad of Celite™ and washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 40 mg (21% yield) of D-34 as off whitesolid.

LCMS-Condition-1: [M+H]⁺=457.10; Rt=1.42 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.08 (s, 1H), 7.88-7.93 (m, 1H), 7.71-7.75(m, 2H), 7.46-7.51 (m, 1H), 7.21 (dd, J=1.90, 8.86 Hz, 1H), 7.03 (d,J=7.95 Hz, 2H), 6.85 (d, J=2.08 Hz, 1H), 6.73-6.77 (m, 2H), 6.69-6.72(m, 1H), 5.15 (d, J=16.63 Hz, 1H), 4.80 (d, J=16.75 Hz, 1H), 2.52-2.69(m, 6H), 0.95 (t, J=7.09 Hz, 3H).2-(2-Chlorophenyl)-1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-1H-indol-5-ol(D-37)

To a solution of 4-(benzyloxy)-2-(2,2-dibromovinyl)aniline D-13-3 (2.5g, 6.52 mmol) in toluene-ethanol (9:1, 50 mL) was added 2-C₁-phenylboronic acid (1.32 g, 8.48 mmol) and a solution of Na₂CO₃ (2.07 g, 19.58mmol) in water (1.5 mL) simultaneously at room temperature under argonatmosphere and degassed for 30 min. To the resulting solution was addedPd(PPh₃)₄ (376 mg, 0.326 mmol) and degassing was continued for another10 min at room temperature. The reaction mixture was then heated at 90°C. for 18 h. After completion of the reaction (monitored by TLC andLCMS), the reaction mixture was diluted with water and extracted withethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-15% ethyl acetate in n-hexane to afford 650 g (30% yield) ofcompound 37-1 as thick yellow liquid.

LCMS-Condition 01: [M+H]⁺=334.35; Rt=2.39 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.70 (br. s, 1H), 7.67 (dd, J=1.6, 7.6 Hz,1H), 7.48-7.51 (m, 3H), 7.39-7.43 (m, 2H), 7.30-7.37 (m, 4H), 7.20 (d,J=2.00 Hz, 1H), 6.98 (dd, J=2.40, 8.80 Hz, 1H), 6.80 (s, 1H), 5.14 (s,2H).

To a solution of 5-(benzyloxy)-2-(2-chlorophenyl)-1H-indole 37-1 (650mg, 1.94 mmol) in dry Acetonitrile-DMSO (1:1, 12 mL) at −10° C. wasadded selectfluor (690 mg, 1.94 mmol) under argon atmosphere. Thereaction mixture was further stirred at 0° C. for 2 h. After completionof the reaction (Monitored by TLC), the reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in ethylacetate (100 mL) and washed with water (40 mL) followed by brine (30mL). The separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-10% ethylacetate in n-hexane followed by preparative TLC to afford 300 mg (44%yield) of compound 37-2 as light brown solid.

LCMS-Condition 01: [M+18]=360.90; Rt=2.38 min

¹H NMR (400 MHz, CDCl₃) δ: 7.87 (d, J=7.6 Hz, 1H), 7.56 (dd, J=1.6, 7.6Hz, 1H), 7.49-7.54 (m, 2H), 7.36-7.44 (m, 6H), 7.22 (d, J=2.0 Hz, 1H),7.06 (dd, J=2.0, 8.4 Hz, 1H).

To 5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indole 37-2 (300 g,0.852 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (60%dispersion in oil, 102 mg, 2.558 mmol) portion wise and stirred at 0° C.for 30 min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (365 mg, 1.108mmol). The reaction mixture was stirred at room temperature for 18 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with ice cold water and extracted withethyl acetate (3×15 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-10% ethyl acetate in n-hexane to afford 280 mg (55% yield) ofcompound 37-3 as yellowish oil.

LCMS-Condition 01: [M+H]⁺=600.35; Rt=2.83 min

¹H NMR (400 MHz, CDCl₃) δ: 7.46-7.53 (m, 2H), 7.28-7.42 (m, 5H),7.17-7.21 (m, 3H), 7.10 (dd, J=2.08, 8.68 Hz, 1H), 7.02 (d, J=8.07 Hz,2H), 6.92 (dd, J=2.45, 8.93 Hz, 1H), 6.79 (d, J=8.07 Hz, 2H), 5.16 (d,J=16.40 Hz, 1H), 5.12 (s, 2H), 4.98 (d, J=16.87 Hz, 1H), 3.79 (t, J=7.09Hz, 2H), 2.82 (d, J=7.2 Hz, 2H), 0.87 (s, 9H), −0.055 (s, 6H).

To5-(benzyloxy)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-2-(2-chlorophenyl)-3-fluoro-1H-indole37-3 (280 mg, 0.466 mmol) in THE (6 mL) at 0° C. was added TBAF (183 mg,0.699 mmol) portion wise. The reaction mixture was further stirred atroom temperature for 1 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (thrice). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-50% ethyl acetate in n-hexane to afford 200 mg (88% yield) ofcompound 37-4 as light brown thick liquid.

LCMS-Condition 01: [M+H]⁺=486.04; Rt=2.39 min

¹H NMR (400 MHz, CDCl₃) δ: 7.50 (dd, J=7.34, 12.23 Hz, 2H), 7.30-7.42(m, 5H), 7.22 (d, J=8.31 Hz, 2H), 7.18 (d, J=2.45 Hz, 1H), 7.13 (dd,J=1.96, 9.29 Hz, 1H), 7.04 (d, J=7.83 Hz, 2H), 6.94 (dd, J=2.20, 9.05Hz, 1H), 6.81 (d, J=8.31 Hz, 2H), 5.15-5.20 (m, 1H), 5.12 (s, 2H),4.99-5.04 (m, 1H), 3.75-3.89 (m, 2H), 2.76-2.87 (m, 2H).

To2-(4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenyl)ethan-1-ol37-4 (250 mg, 0.514 mmol) in CH₂Cl₂ (mL) at 0° C. was addedtriethylamine (0.21 mL, 1.543 mmol) followed by TsCl (127 mg, 0.668mmol). The reaction mixture was stirred at room temperature for 2 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with sodium bicarbonate solution andextracted with ethyl acetate (3×20 mL). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-20% ethyl acetate in n-hexane to afford300 mg (91% yield) of compound 37-5 as off white solid.

LCMS-Condition 01: [M+H]⁺=640.20; Rt=2.47 min

¹H NMR (400 MHz, CDCl₃) δ: 7.45-7.54 (m, 3H), 7.29-7.42 (m, 6H),7.17-7.24 (m, 4H), 7.08-7.12 (m, 2H), 6.90-6.95 (m, 3H), 6.76 (d, J=8.31Hz, 2H), 5.16 (d, J=16.63 Hz, 1H), 5.12 (s, 2H), 4.98 (d, J=16.63 Hz,1H), 2.95 (t, J=7.09 Hz, 2H), 2.86 (t, J=7.09 Hz, 2H), 2.39 (s, 3H).

To a solution of4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl4-methylbenzenesulfonate 37-5 (200 mg, 0.312 mmol) in acetonitrile (3mL) was added cyclopropanamine (178 mg, 3.124 mmol) and DIPEA (0.54 mL,3.124 mmol) in a sealed tube. Then the reaction mixture was stirred atroom temperature for 72 h. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was diluted with water andextracted with ethyl acetate (3×100 mL). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-50% ethyl acetate in n-hexane to afford 90mg (55% yield) of compound 37-6 as off white sticky solid.

LCMS-Condition 01: [M+H]⁺=525.15; Rt=1.83 min

¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.53 (m, 2H), 7.30-7.42 (m, 5H), 7.29(d, J=2.45 Hz, 1H), 7.17-7.22 (m, 2H), 7.14 (dd, J=1.96, 8.80 Hz, 1H),7.02 (d, J=7.83 Hz, 2H), 6.94 (dd, J=2.45, 8.80 Hz, 1H), 6.79 (d, J=7.83Hz, 2H), 5.14-5.20 (m, 1H), 5.12 (s, 2H), 4.98-5.04 (m, 1H), 2.93-2.99(m, 1H), 2.86-2.91 (m, 1H), 2.78-2.84 (m, 1H), 2.68-2.74 (m, 1H),2.10-2.14 (m, 1H), 0.33-0.45 (m, 4H).

To a solution ofN-(4-((5-(benzyloxy)-2-(2-chlorophenyl)-3-fluoro-1H-indol-1-yl)methyl)phenethyl)cyclopropanamine37-6 (90 mg, 0.171 mmol) in ethyl acetate-methanol (2:1, 3 mL) was added20% palladium hydroxide on carbon (30 mg) at room temperature. Then thereaction mixture was stirred under hydrogen atmosphere for 18 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was filtered through a pad of Celite™ and washed with ethylacetate. The filtrate was concentrated under reduced pressure and thecrude compound was purified by preparative HPLC to afford 14 mg (19%yield) of D-37 as white solid.

LCMS-Condition 01: [M+H]⁺=435.10; Rt=1.51 min

¹H NMR (400 MHz, CDCl₃) δ: 7.51 (dd, J=1.00, 8.03 Hz, 1H), 7.29-7.39 (m,3H), 7.00-7.12 (m, 4H), 6.74-6.82 (m, 3H), 5.12-5.18 (m, 1H), 4.95-5.03(m, 1H), 2.86-2.92 (m, 2H), 2.68-2.76 (m, 2H), 2.08-2.13 (m, 1H),0.81-0.91 (m, 2H), 0.40-0.47 (m, 2H).N-Ethyl-2-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine(D-85)

To 5-nitro-1H-indazole 85-1 (10 g, 61.29 mmol) in THE (100 mL) was addedsodium hydroxide (6.1 g, 153.2 mmol) followed by n-tetrabutyl ammoniumsulfate (312 mg, 0.917 mmol) and stirred for 1 h at room temperature. Tothe resulting solution was added benzene sulfonyl chloride (12 g, 67.79mmol) drop wise and stirred for another 1 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was quenchedwith water and extracted with ethyl acetate (3×100 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting crude compound was purified bytrituration in diethyl ether to afford 17.3 g (93% yield) of compound85-2 as white solid.

LCMS: [M+H]⁺=303.95; Rt=1.85 min

¹H NMR (400 MHz, CDCl₃) δ: 8.66 (d, J=1.96 Hz, 1H), 8.44-8.47 (m, 1H),8.34-8.38 (m, 2H), 8.02-8.06 (m, 2H), 7.62-7.67 (m, 1H), 7.50-7.55 (m,2H).

To a solution of 5-nitro-1-(phenylsulfonyl)-1H-indazole 85-2 (17.3 g,57.09 mmol) in methanol (200 mL) was added hydrazine hydrate (10 g,199.8 mmol) and 20% palladium on carbon (2 g) at room temperature. Thereaction mixture was heated at 70° C. for 3 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was filteredthrough a pad of Celite™ and the filtrate was concentrated under reducedpressure. The crude compound was purified by trituration in diethylether to afford 14.5 g (93% yield) of compound 85-3 as light brownsolid.

LCMS: [M+H]⁺=274.15; Rt=1.43 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (s, 1H), 7.76-7.84 (m, 3H), 7.64-7.71(m, 1H), 7.52-7.59 (m, 2H), 6.96 (dd, J=1.96, 8.80 Hz, 1H), 6.77 (d,J=1.96 Hz, 1H), 5.30 (s, 2H).

To a solution of 1-(phenylsulfonyl)-1H-indazol-5-amine 85-3 (14.5 g,53.11 mmol) in acetonitrile (300 mL) was added N-iodosuccinimide (14.3g, 63.73 mmol) at room temperature and stirred for 2 h. After completionof the reaction (monitored by TLC and LCMS), the reaction mixture wasdiluted with water and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure, crude compound was purified bysilica gel column chromatography eluting with 10-15% ethyl acetate inn-hexane to afford 11 g (52% yield) of compound 85-4 as off white solid.

LCMS: [M+H]⁺=399.90; Rt=1.97 min

¹H NMR (400 MHz, DMSO-d₆) δ: 8.07-8.10 (m, 1H), 7.83-7.88 (m, 3H),7.68-7.74 (m, 1H), 7.54-7.62 (m, 2H), 7.11 (d, J=9.29 Hz, 1H), 5.48 (s,2H).

To 4-iodo-1-(phenylsulfonyl)-1H-indazol-5-amine 85-4 (6 g, 15.03 mmol)in CH₂Cl₂ (50 mL) at 0° C. was added triethylamine (8 mL, 57.56 mmol)and TFAA (4 mL, 28.57 mmol). The reaction mixture was then stirred atroom temperature for 2 h. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was diluted with water and extractedwith CH₂Cl₂ (3×50 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 5.5 g (71% yield) ofcompound 85-5 as off white solid.

LCMS: [M+H]⁺=495.90; Rt=2.06 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.43 (s, 1H), 8.45 (s, 1H), 8.20 (d,J=8.80 Hz, 1H), 7.96-8.01 (m, 2H), 7.73-7.79 (m, 1H), 7.60-7.67 (m, 3H).

To2,2,2-trifluoro-N-(4-iodo-1-(phenylsulfonyl)-1H-indazol-5-yl)acetamide85-5 (5.5 g, 11.11 mmol) in DMF (75 mL) was added copper iodide (212 mg,1.115 mmol) followed by triethylamine (7.7 mL, 55.55 mmol) at roomtemperature and degassed with argon for 15 min. To the resultingsolution was added dichlorobis(triphenylphosphine)palladium(II) (779 mg,1.112 mmol) and 1-ethynyl-2-methylbenzene (1.54 g, 13.33 mmol) anddegassing was continued for another 10 min. The reaction mixture wasthen heated at 130° C. for 18 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was filtered through apad of Celite™ and the filtrate was diluted with water and extractedwith ethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure;crude compound was purified by Combiflash column chromatography elutingwith 10-20% ethyl acetate in n-hexane to afford 3.5 g (81% yield) ofcompound 85-6 as white solid.

LCMS: [M+H]⁺=388.30; Rt=2.08 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.87 (s, 1H), 8.74 (s, 1H), 7.87-7.93 (m,3H), 7.72 (d, J=8.80 Hz, 1H), 7.56 (t, J=7.83 Hz, 3H), 7.29-7.38 (m,4H), 6.94 (d, J=1.47 Hz, 1H), 2.47 (s, 3H).

To 3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole 85-6(1 g, 2.583 mmol) in dry Acetonitrile:DMSO (4:1, 50 mL) at −10° C. wasadded selectfluor (1.28 g, 3.617 mmol) under argon atmosphere. Thereaction mixture was further stirred at −10° C. for 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was quenched with water and extracted with ethyl acetate (3×20mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by Combiflash column chromatography eluting with 0-20% ethylacetate in n-hexane to afford 450 mg (43% yield) of compound 85-7 aslight yellow solid.

LCMS: [M+H]⁺=406.35; Rt=2.13 min

¹H NMR (400 MHz, DMSO-d₆) δ: 11.80 (s, 1H), 8.68 (s, 1H), 7.98 (d,J=9.29 Hz, 1H), 7.89-7.92 (m, 2H), 7.68-7.72 (m, 2H), 7.55-7.61 (m, 2H),7.46 (d, J=6.85 Hz, 1H), 7.33-7.39 (m, 3H), 2.36 (s, 3H).

To8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole85-7 (450 mg, 1.111 mmol) in DMF (10 mL) at 0° C. was added sodiumhydride (60% dispersion in oil, 53 mg, 2.222 mmol) portion wise andstirred for 30 min. To the resulting solution was added(4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane (437 mg, 1.333mmol). The reaction mixture was stirred at room temperature for 1 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with water and extracted with ethylacetate (3×20 mL). The combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by Combiflash column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 850 mg (100% yield) ofcompound 85-8 as light yellow solid.

LCMS: [M+H]⁺=655.60; Rt=2.73 min

¹H NMR (400 MHz, CDCl₃) δ: 8.47-8.49 (m, 1H), 7.98-8.03 (m, 2H),7.52-7.57 (m, 1H), 7.41-7.47 (m, 3H), 7.31 (d, J=8.31 Hz, 2H), 7.23 (d,J=3.42 Hz, 2H), 7.18 (d, J=7.83 Hz, 1H), 7.03 (d, J=8.31 Hz, 2H), 6.74(d, J=7.82 Hz, 2H), 5.20-5.25 (m, 1H), 5.09-5.15 (m, 1H), 3.79 (t,J=6.85 Hz, 2H), 2.73 (t, J=6.85 Hz, 2H), 2.16 (s, 3H), 0.83 (s, 9H),0.00 (s, 6H).

To a solution of6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)-3,6-dihydropyrrolo[3,2-e]indazole85-8 (850 mg, 1.301 mmol) in THF (15 mL) at 0° C. was addedtetrabutylammonium fluoride solution (1M in THF, 2 mL, 1.952 mmol). Thereaction mixture was stirred at room temperature for 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was quenched with water and extracted with ethyl acetate (3×30mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by Combiflash column chromatography eluting with 30-40% ethylacetate in n-hexane to afford 360 mg (51% yield) of compound 85-9 as offwhite solid.

LCMS: [M+H]⁺=540.65; Rt=2.17 min

¹H NMR (400 MHz, CDCl₃) δ: 8.48 (s, 1H), 7.98-8.05 (m, 3H), 7.52-7.57(m, 1H), 7.42-7.48 (m, 3H), 7.29-7.35 (m, 2H), 7.24 (d, J=3.45 Hz, 2H),7.06 (d, J=7.88 Hz, 2H), 6.77 (d, J=7.88 Hz, 2H), 5.13-5.27 (m, 2H),3.77-3.84 (m, 2H), 2.79 (t, J=6.40 Hz, 2H), 2.15 (s, 3H).

To a solution of2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-ol85-9 (350 mg, 0.649 mmol) in CH₂Cl₂ (20 mL) at 0° C. was addedtriethylamine (0.23 mL, 1.948 mmol) followed by tosyl chloride (148 mg,0.779 mmol). The reaction mixture was stirred at room temperature for 18h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with water and extracted with ethylacetate (2×20 mL). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by Combiflash column chromatography eluting with0-20% ethyl acetate in n-hexane to afford 370 mg (45% yield) of compound85-10 as light yellow solid.

LCMS: [M+H]⁺=694.30; Rt=2.39 min

¹H NMR (400 MHz, CDCl₃) δ: 8.49 (s, 1H), 8.03 (d, J=9.35 Hz, 1H),7.98-8.01 (m, 2H), 7.65 (d, J=8.37 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.47(m, 4H), 7.30-7.37 (m, 2H), 7.23 (s, 1H), 7.19 (d, J=7.88 Hz, 2H), 6.95(d, J=7.88 Hz, 2H), 6.72 (d, J=7.88 Hz, 2H), 5.19-5.26 (m, 1H),5.07-5.15 (m, 1H), 4.13 (t, J=7.14 Hz, 2H), 2.87 (t, J=6.89 Hz, 2H),2.37 (s, 3H), 2.15 (s, 3H).

To4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl4-methylbenzenesulfonate 85-10 (120 mg, 0.173 mmol) inacetonitrile-water (1:1, 4 mL) was added ethyl amine solution (2M inTHF, 1.06 mL, 2.120 mmol) at room temperature and stirred for 72 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was concentrated and diluted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 4-6% methanolin CH₂Cl₂ to afford 95 mg (97% yield) of compound 85-11 as white solid.

LCMS: [M+H]⁺=567.20; Rt=1.64 min

To a solution ofN-ethyl-2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine85-11 (93 mg, 0.1643 mmol) in methanol (4 mL) was added a solution ofpotassium carbonate (90.6 mg, 0.657 mmol) in water (1 mL) at roomtemperature. The reaction mixture was heated to reflux for 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 23 mg (33% yield) of D-85 asoff white solid.

LCMS: [M+H]⁺=427.25; Rt=1.39 min

¹H NMR (400 MHz, CDCl₃) δ: 8.34 (s, 1H), 7.21-7.38 (m, 6H), 7.01 (d,J=8.31 Hz, 2H), 6.75 (d, J=7.83 Hz, 2H), 5.09-5.25 (m, 2H), 2.83-2.88(m, 2H), 2.74-2.78 (m, 2H), 2.70 (q, J=7.17 Hz, 2H), 2.19 (s, 3H), 1.11(t, J=7.09 Hz, 3H).

N-(Cyclopropylmethyl)-2-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine(D-88)

To a solution of4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl4-methylbenzenesulfonate 85-10 (120 mg, 0.173 mmol) in acetonitrile (10mL) was added cyclopropyl methyl amine (122 mg, 1.731 mmol) and DIPEA(0.3 mL, 1.731 mmol) in a sealed tube. The reaction mixture was stirredat room temperature for 72 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was concentrated anddiluted with ethyl acetate. Organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude compound was purified by Combiflash column chromatographyeluting with 0-6% methanol in CH₂Cl₂ to afford 90 mg (88% yield) ofcompound 88-1 as white solid.

LCMS: [M+H]⁺=593.20; Rt=1.88 min

To a solution ofN-(cyclopropylmethyl)-2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine88-1 (90 mg, 0.152 mmol) in methanol (4 mL) was added a solution ofpotassium carbonate (83.7 mg, 0.607 mmol) in water (1 mL) at roomtemperature. The reaction mixture was heated to reflux 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 25 mg (36% yield) of D-88 asoff white solid.

LCMS: [M+H]⁺=453.25; Rt=1.45 min

¹H NMR (400 MHz, CDCl₃) δ: 8.34 (s, 1H), 7.23-7.37 (m, 6H), 7.02 (d,J=7.6 Hz, 2H), 6.76 (d, J=8.31 Hz, 2H), 5.12-5.26 (m, 2H), 2.85-2.91 (m,2H), 2.73-2.79 (m, 2H), 2.51 (d, J=6.85 Hz, 2H), 2.20 (s, 3H), 0.87-0.98(m, 1H), 0.42-0.51 (m, 2H), 0.05-0.14 (m, 2H).N-(4-((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclobutanamine(D-89)

To a solution of4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl-4-methylbenzenesulfonate85-10 (120 mg, 0.173 mmol) in acetonitrile (10 mL) was addedcyclobutanamine (124 mg, 1.7316 mmol) and DIPEA (0.3 mL, 1.7316 mmol) ina sealed tube. The reaction mixture was stirred at room temperature for72 h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was concentrated and diluted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by Combiflash column chromatography eluting with 0-10% methanolin CH₂Cl₂ to afford 101 mg (99% yield) of compound 89-1 as white solid.

LCMS: [M-18]⁺=575.25; Rt=1.66 min

To a solution ofN-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclobutanamine89-1 (85 mg, 0.150 mmol) in methanol (4 mL) was added a solution ofpotassium carbonate (83 mg, 0.600 mmol) in water (1 mL) at roomtemperature. The reaction mixture was heated to reflux for 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 30 mg (44% yield) of D-89 asoff white solid.

LCMS: [M+H]⁺=453.25; Rt=1.45 min

¹H NMR (400 MHz, CDCl₃) δ: 8.34 (s, 1H), 7.27-7.38 (m, 5H), 7.21-7.25(m, 1H), 7.01 (d, J=7.83 Hz, 2H), 6.75 (d, J=7.82 Hz, 2H), 5.09-5.25 (m,2H), 3.22-3.30 (m, 1H), 2.67-2.78 (m, 4H), 2.20 (s, 3H), 2.15-2.18 (m,2H), 1.62-1.69 (m, 5H).

N-(4-((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclopropanamine(D-90)

To a solution of4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl4-methylbenzenesulfonate 85-10 (120 mg, 0.173 mmol) in acetonitrile (10mL) was added cyclopropanamine (98.7 mg, 1.731 mmol) and DIPEA (0.3 mL,1.731 mmol) in a sealed tube. The reaction mixture was stirred at roomtemperature for 72 h. After completion of the reaction (monitored by TLCand LCMS), the reaction mixture was concentrated and diluted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by Combiflash column chromatography eluting with0-10% methanol in CH₂Cl₂ to afford 100 mg (99% yield) of compound 90-1as white solid.

LCMS: [M+H]⁺=579.20; Rt=1.65 min

To a solution ofN-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclopropanamine90-1 (105 mg, 0.181 mmol) in methanol (4 mL) was added a solution ofpotassium carbonate (100 mg, 0.726 mmol) in water (1 mL) at roomtemperature. The reaction mixture was heated to reflux for 2 h. Aftercompletion of the reaction (monitored by TLC and LCMS), the reactionmixture was concentrated under reduced pressure and the crude compoundwas purified by preparative HPLC to afford 32 mg (40% yield) of D-90 asoff white solid.

LCMS: [M+H]⁺=439.20; Rt=1.42 min

¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.27-7.37 (m, 6H), 7.22-7.25(m, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.76 (d, J=8.31 Hz, 2H), 5.10-5.26 (m,2H), 2.86-2.92 (m, 2H), 2.69-2.74 (m, 2H), 2.20 (s, 3H), 2.07-2.12 (m,1H), 0.39-0.45 (m, 2H), 0.29-0.35 (m, 2H).

N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine(D-91)

To4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl4-methylbenzenesulfonate D-85-10 (120 mg, 0.173 mmol) in acetonitrile(10 mL) was added propan-1-amine (102 mg, 1.731 mmol) and DIPEA (0.3 mL,1.731 mmol) in a seal tube. The reaction mixture was further stirred atroom temperature for 72 h. After completion of the reaction, thereaction mixture was diluted with water and extracted with ethyl acetate(2×10 mL). The combined organic layer dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by Combiflash column chromatography eluting with 0-10% methanolin CH₂Cl₂ to afford 85 mg (85% yield) of compound 91-1 as off whitesolid.

LCMS: [M+H]⁺=581.25; Rt=1.86 min

ToN-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine91-1 (85 mg, 0.146 mmol) in methanol (4 mL) was added solution ofpotassium carbonate (81 mg, mmol) in water (1 mL) at room temperature.The reaction mixture was further heated to reflux at 70° C. and stirredfor 2 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure and the crude compound was purifiedby preparative HPLC to afford 20 mg (31% yield) of D-91 as off whitesolid.

LCMS: [M+H]⁺=441.20; Rt=1.62 min

¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.52 (s, 1H), 7.28-7.37 (m,4H), 7.20-7.23 (m, 1H), 6.99-7.03 (m, 2H), 6.76 (d, J=7.82 Hz, 2H),5.10-5.26 (m, 2H), 3.49 (s, 1H), 2.77-2.84 (m, 2H), 2.70-2.76 (m, 2H),2.56 (t, J=7.34 Hz, 2H), 2.20 (s, 3H), 1.43-1.50 (m, 2H), 0.87 (t,J=7.34 Hz, 3H).

2-Fluoro-N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)ethan-1-amine(D-101)

To4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl4-methylbenzenesulfonate 85-10 (170 mg, 0.245 mmol) in DMF (5 mL) wasadded potassium pthalimide (43.2 mg, 0.294 mmol) at room temperature.The reaction mixture was further heated to 90° C. and stirred for 3 h.After completion of the reaction, the reaction mixture was cooled toroom temperature, quenched with water and extracted with ethyl acetate(3×20 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford 155 mg (95%yield) of compound 101-11 as brown solid.

LCMS-Condition-1: [M+H]⁺=669.20; Rt=2.40 min

To2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)isoindoline-1,3-dione101-11 (2 g, 2.990 mmol) in ethanol (40 mL) was added hydrazine hydrate(143 mg, 4.486 mmol) at room temperature. The reaction mixture wasfurther heated to 80° C. and stirred for 1 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure,the DCM for 15 min and filtered. The filtrate was concentrated underreduced pressure resulting in the crude compound which was purified bysilica gel column chromatography eluting with 0-5% methanol in DCM toafford 1.1 g (68% yield) of compound 101-12 as yellow solid.

LCMS-Condition-1: [M-18]⁺=521.10; Rt=1.61 min

To2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine101-12 (550 mg, 1.021 mmol) in acetonitrile (4 mL) was added DIPEA (1.77mL, 10.21 mmol) and 1-fluoro-2-iodoethane (1.8 g, 10.21 mmol) at roomtemperature and stirred for 48 h. After completion of the reaction, thereaction mixture was diluted with water and extracted with DCM (3×25mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-2% methanolin DCM to afford 380 mg (63% yield) of compound 101-13A as light yellowsolid.

LCMS-Condition-1: [M+H]⁺=585.15; Rt=1.71 min

¹H NMR (400 MHz, CDCl₃) δ: 8.39-8.50 (m, 1H), 7.96-8.05 (m, 3H),7.50-7.58 (m, 1H), 7.44 (t, J=8.07 Hz, 3H), 7.28-7.38 (m, 2H), 7.20-7.24(m, 2H), 7.04 (d, J=7.82 Hz, 2H), 6.72-6.81 (m, 2H), 5.10-5.26 (m, 2H),4.61 (t, J=4.40 Hz, 1H), 4.49 (t, J=4.40 Hz, 1H), 2.98 (t, J=4.16 Hz,1H), 2.90 (t, J=6.85 Hz, 3H), 2.75-2.83 (m, 2H), 2.14 (s, 2H), 2.11 (s,1H).

To2-fluoro-N-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)ethan-1-amine101-13A (200 mg, 0.342 mmol) in methanol (4 mL) was added potassiumcarbonate (189 mg, 1.369 mmol) at room temperature. The reaction mixturewas further heated to reflux at 60° C. and stirred for 3 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with DCM (3×25 mL). The combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureresulting in the crude compound. The crude compound was purified bysilica gel column chromatography eluting with 0-6% methanol in DCM toafford 10 mg (6.5% yield) of D-101 as off white solid.

LCMS-Condition-1: [M+H]⁺=445.20; Rt=1.39 min

¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 7.30-7.36 (m, 2H), 7.26 (2Hmerged in solvent peak), 7.19-7.24 (m, 2H), 7.01 (d, J=7.83 Hz, 2H),6.75 (d, J=7.83 Hz, 2H), 5.07-5.25 (m, 2H), 4.62 (t, J=4.40 Hz, 1H),4.48-4.54 (m, 1H), 3.03-3.07 (m, 1H), 2.95-3.01 (m, 3H), 2.80 (t, J=7.09Hz, 2H), 2.19 (s, 3H).

3-Fluoro-N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine(D-102)

To a solution of2-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine101-12 (200 mg, 0.371 mmol) in acetonitrile (3 mL) was added DIPEA (0.16mL, 0.742 mmol) and 1-fluoro-3-iodopropane (70 mg, 0.371 mmol) at roomtemperature and stirred for 48 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was diluted with waterand extracted with DCM (3×25 mL). The combined organic layer was washedwith water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-2% methanol in DCM toafford 90 mg (40% yield) of compound 102-13B as light yellow solid.

LCMS-Condition-1: [M+H]⁺=599.15; Rt=1.67 min

¹H NMR (400 MHz, CDCl₃) δ: 8.48 (s, 1H), 7.98-8.05 (m, 2H), 7.52-7.59(m, 1H), 7.45 (t, J=8.07 Hz, 2H), 7.23-7.39 (m, 6H), 7.05 (d, J=7.82 Hz,2H), 6.76 (d, J=7.34 Hz, 2H), 5.09-5.26 (m, 2H), 4.57 (t, J=5.38 Hz,1H), 4.46 (t, J=5.38 Hz, 1H), 2.88-3.02 (m, 4H), 2.15 (s, 3H), 1.98-2.05(m, 2H), 0.87-0.91 (m, 2H).

To a solution of3-fluoro-N-(4-((8-fluoro-3-(phenylsulfonyl)-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine102-13B (90 mg, 0.150 mmol) in methanol (3 mL) was added potassiumcarbonate (72 mg, 0.526 mmol) at room temperature. The reaction mixturewas heated to reflux for 20 min. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withwater and extracted with ethyl acetate (3×25 mL). The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-3% methanol in DCM,followed by trituration in diethyl ether and n-pentane to afford 30 mg(43% yield) of D-102 as off white solid.

LCMS-Condition-1: [M+H]⁺=459.60; Rt=1.41 min

¹H NMR (400 MHz, CDCl₃) δ: 8.35 (s, 1H), 7.27-7.36 (m, 5H), 7.21-7.24(m, 1H), 7.02 (d, J=7.82 Hz, 2H), 6.76 (d, J=7.82 Hz, 2H), 5.09-5.26 (m,2H), 4.53 (t, J=5.87 Hz, 1H), 4.41 (t, J=5.87 Hz, 1H), 2.78-2.84 (m,2H), 2.69-2.75 (m, 4H), 2.20 (s, 3H), 1.76-1.90 (m, 4H).

(5R,6S)-5-(4-(2-(Ethylamino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol(LA-18)

A mixture of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one L18-1 (20 g,120.5 mmol), benzyl bromide (22.7 g, 144.5 mmol) and cesium carbonate(117 g, 359.1 mmol) in xylene (200 mL) was degassed with argon for 15min in a seal tube at room temperature. To the resulting solution wasadded Pd(OAc)₂ (1.34 g, 5.982 mmol) and Xanthphos (3.5 g, 6.055 mmol)and degassing was continued for another 15 min. The reaction mixture wassealed properly and heated to 130° C. for 24 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was dilutedwith water and extracted with ethyl acetate (3×). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-10% ethyl acetate in n-hexaneto afford 10 g (33% yield) of compound L18-2 as off white solid.

LCMS-Condition 01: [M+H]⁺=253.05; Rt=1.95 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.87 (d, J=9.29 Hz, 1H), 7.29-7.34 (m, 2H),7.22-7.26 (m, 1H), 7.17 (d, J=7.34 Hz, 2H), 6.89-6.95 (m, 2H), 3.88 (d,J=4.89 Hz, 1H), 3.85 (s, 3H), 3.06-3.16 (m, 1H), 2.95 (td, J=4.04, 16.87Hz, 1H), 2.21-2.39 (m, 2H).

To a solution of 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-oneL18-2 (10 g, 36.76 mmol) in toluene (100 mL) was added PBr₃ (12 g, 44.42mmol) at room temperature. The reaction mixture was heated to reflux for16 h. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with water and extracted with ethylacetate (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-5% ethyl acetate in n-hexane to afford 9 g (77% yield) ofcompound L18-3 as white solid.

LCMS-Condition 01: [M+H]⁺=315.00; Rt=2.46 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.50-7.55 (m, 1H), 7.35-7.43 (m, 4H),7.29-7.35 (m, 1H), 6.84-6.88 (m, 2H), 3.79 (s, 3H), 2.88-2.95 (m, 2H),2.63-2.69 (m, 2H).

To a solution of 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene L18-3(2 g, 6.349 mmol) and2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol(1.57 g, 6.349 mmol) in DMF (40 mL) was added solution of cesiumcarbonate (6.2 g, 19.04 mmol) in water (8 mL) and degassed with argonfor 20 min in a seal tube. To the resulting solution was added palladiumacetate (71 mg, 0.316 mmol) followed by TPP (166 mg, 0.633 mmol) anddegassing was continued for another 15 min. The reaction mixture washeated at 100° C. for 16 h. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was cooled to room temperatureand quenched with ice cold water and extracted with ethyl acetate (3×).The combined organic layer dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude compound waspurified by silica gel column chromatography eluting with 0-15% ethylacetate in n-hexane to afford 1 g (44% yield) of compound L18-4 asyellow solid.

LCMS-Condition-1: [M+H]⁺=357.10; Rt=2.31 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.09 (d, J=7.34 Hz, 4H), 7.04 (d, J=6.85Hz, 1H), 6.99-7.03 (m, 2H), 6.90 (d, J=8.31 Hz, 2H), 6.85 (d, J=1.96 Hz,1H), 6.64 (dd, J=2.45, 8.31 Hz, 1H), 6.51 (d, J=8.80 Hz, 1H), 4.63 (t,J=5.38 Hz, 1H), 3.74 (s, 3H), 3.56-3.64 (m, 2H), 2.87-2.94 (m, 2H), 2.69(t, J=7.34 Hz, 4H).

To a solution of2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-olL18-4 (600 mg, 1.683 mmol) in DCM (10 mL) was added triethylamine (0.9mL, 6.734 mmol) and tosyl chloride (481 mg, 2.525 mmol) at roomtemperature and stirred for 18 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withwater and extracted with ethyl acetate₂ (3×). Combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-15% ethyl acetate in n-hexane to afford600 mg (70% yield) of compound L18-5 as colourless sticky solid.

LCMS-Condition-1: [M+H]⁺=511.20; Rt=2.60 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.76 (d, J=8.31 Hz, 2H), 7.48 (d, J=8.31Hz, 2H), 7.02-7.17 (m, 7H), 6.95 (d, J=7.83 Hz, 2H), 6.90 (d, J=2.45 Hz,1H), 6.69 (dd, J=2.69, 8.56 Hz, 1H), 6.52 (d, J=8.31 Hz, 1H), 4.26 (t,J=6.36 Hz, 2H), 3.79 (s, 3H), 2.89-2.98 (m, 4H), 2.72-2.77 (m, 2H), 2.45(s, 3H).

To a solution of4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L18-5 (300 mg, 0.587 mmol) in acetonitrile (2mL) was added ethyl amine (240 mg, 5.876 mmol) and DIPEA (1.02 mL, 5.786mmol) in a seal tube. The reaction mixture was further stirred at roomtemperature for 3 days. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was diluted with water and extractedwith ethyl acetate (2×). Combined organic layer dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-10% methanol in CH₂Cl₂ to afford 160 mg (71% yield) of compound L18-6as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=384.20; Rt=1.81 min

To a solution ofN-ethyl-2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-amineL18-6 (160 mg, 0.417 mmol) in ethyl acetate (20 mL) was added 10%palladium on carbon (200 mg) at room temperature under nitrogenatmosphere. The reaction mixture was stirred under hydrogen atmosphereat room temperature for 18 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was filtered through apad of Celite™ and washed with methanol. The filtrate was concentratedunder reduced pressure to afford 150 mg (94% yield) of L18-7 ascolourless sticky solid.

LCMS-Condition-1: [M+H]⁺=386.20; Rt=1.39/1.83 min

ToN-ethyl-2-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amineL18-7 (150 mg, 0.389 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added borontribromide (0.07 mL, 0.770 mmol) drop wise. The reaction mixture wasstirred at same temperature for 45 min. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withsaturated NaHCO₃ solution, and extracted with CH₂Cl₂ (3×). The separatedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by preparativeHPLC to afford 62 mg (43% yield) of LA-18 (TFA salt) as off white solid.

LCMS-Condition-1: [M+H]⁺=372.20; Rt=1.62 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (br. s, 1H), 8.36 (br. s, 2H),7.10-7.17 (m, 3H), 6.80-6.88 (m, 3H), 6.59-6.66 (m, 2H), 6.49 (dd,J=2.45, 8.31 Hz, 1H), 6.35 (d, J=8.31 Hz, 2H), 4.21-4.26 (m, 1H),3.43-3.58 (m, 2H), 3.35 (dd, J=3.91, 12.23 Hz, 1H), 2.88-3.08 (m, 5H),2.69-2.77 (m, 2H), 2.01-2.17 (m, 1H), 1.69-1.77 (m, 1H), 1.15 (t, J=7.34Hz, 3H).

(5R,6S)-5-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol(LA-19)

To a solution of4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L18-5 (300 mg, 0.587 mmol) in acetonitrile (2mL) was added cyclopropylmethanamine (417 mg, 5.876 mmol) and DIPEA(1.02 mL, 5.876 mmol) in a seal tube. The reaction mixture was stirredat room temperature for 3 days. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was diluted with waterand extracted with ethyl acetate (2×). Combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude compound was purified by silica gel column chromatographyeluting with 0-10% methanol in CH₂Cl₂ to afford 160 mg (66% yield) ofcompound L19-6 as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=410.20; Rt=1.86 min

To a solution ofN-(cyclopropylmethyl)-2-(4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-amineL19-6 (160 mg, 0.390 mmol) in ethyl acetate (20 mL) was added 10%palladium on carbon (200 mg) at room temperature under nitrogenatmosphere. The reaction mixture was further stirred at room temperatureunder hydrogen atmosphere for 18 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was filtered through apad of Celite™ and washed with methanol. The filtrate was concentratedunder reduced pressure to afford 150 mg (94% yield) of compound L19-7 ascolourless sticky solid.

LCMS-Condition-1: [M+H]⁺=412.25; Rt=1.89 min

To a solution ofN-(cyclopropylmethyl)-2-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amineL19-7 (150 mg, 0.364 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added borontribromide (0.07 mL, 0.729 mmol) drop wise. The reaction mixture wasstirred at same temperature for 45 min. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withsaturated NaHCO₃ solution, and extracted with CH₂Cl₂ (3×). The separatedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by preparativeHPLC to afford 34 mg (24% yield) of LA-19 (TFA salt) as off white solid.

LCMS-Condition-1: [M+H]⁺=398.25; Rt=1.68 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (br. s, 1H), 8.49 (br. s, 2H),7.08-7.18 (m, 3H), 6.84 (dd, J=8.07, 11.49 Hz, 4H), 6.60-6.65 (m, 2H),6.48 (dd, J=1.96, 8.31 Hz, 1H), 6.35 (d, J=7.82 Hz, 2H), 4.24 (d, J=4.89Hz, 1H), 3.35 (dd, J=2.93, 13.20 Hz, 1H), 2.92-3.08 (m, 4H), 2.72-2.84(m, 4H), 2.02-2.15 (m, 1H), 1.70-1.78 (m, 1H), 0.99 (ddd, J=4.65, 8.07,12.23 Hz, 1H), 0.53-0.60 (m, 2H), 0.28-0.35 (m, 2H).

(5R,6S)-5-(4-(2-(Ethylamino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol(LA-21)

A mixture of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one L18-1 (5 g, 28.41mmol), 2-bromo toluene (5 mL, 42.10 mmol) and cesium carbonate (32.4 g,99.41 mmol) in xylene (125 mL) was degassed with argon for 10 min. Tothe resulting solution was added Pd(OAc)₂ (636 mg, 2.839 mmol) andXanthphos (2.5 g, 4.251 mmol) and degassing with argon was continued foranother 15 min at room temperature. The reaction mixture was heated at130° C. for 24 h. After completion of the reaction (monitored by TLC andLCMS), the reaction mixture was cooled to room temperature and filtered;the filtrate was concentrated under reduced pressure. The resultingcrude material was purified by silica gel column chromatography elutingwith 0-8% ethyl acetate in n-hexane to afford 3.3 g (44% yield) ofcompound L21-2 as yellow solid.

LCMS-Condition 01: [M+H]⁺=267.05; Rt=2.18 min

¹H NMR (400 MHz, CDCl₃) δ: 8.09 (d, J=8.80 Hz, 1H), 7.13-7.27 (m, 3H),7.02-7.08 (m, 1H), 6.87 (dd, J=2.45, 8.80 Hz, 1H), 6.75 (d, J=2.45 Hz,1H), 3.90-3.99 (m, 1H), 3.88 (s, 3H), 2.97-3.15 (m, 2H), 2.35-2.45 (m,2H), 2.32-2.35 (m, 3H).

To a solution of 6-methoxy-2-(o-tolyl)-3,4-dihydronaphthalen-1(2H)-oneL21-2 (8.2 g, 30.76 mmol) in toluene (150 mL) at 0° C. was added PBr₃ (2mL, 21.42 mmol) drop wise. The reaction mixture was then heated toreflux for 16 h. After completion of the reaction (monitored by TLC andLCMS), the reaction mixture was washed with saturated NaHCO₃ solutionand the separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The resulting crudecompound was purified by silica gel column chromatography eluting with0-8% ethyl acetate in n-hexane to afford 7 g (69% yield) of compoundL21-3 as off white solid.

LCMS-Condition 01: [M+H]⁺=329.30; Rt=2.53 min

¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J=8.80 Hz, 1H), 7.17-7.26 (m, 3H),7.08-7.12 (m, 1H), 6.79 (dd, J=2.69, 8.56 Hz, 1H), 6.73 (d, J=2.45 Hz,1H), 3.84 (s, 3H), 2.87-3.04 (m, 2H), 2.54-2.61 (m, 2H), 2.30 (s, 3H).

To a solution of 4-bromo-7-methoxy-3-(o-tolyl)-1,2-dihydronaphthaleneL21-3 (2 g, 6.079 mmol) and2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol (1.5g, 6.079 mmol) in DMF (40 mL) was added a solution of cesium carbonate(5.9 g, 18.23 mmol) in water (8 mL) and degassed with argon for 20 minin a seal tube. To the resulting solution was added palladium acetate(68 mg, 0.304 mmol) and TPP (166 mg, 0.633 mmol) and degassing wascontinued for another 15 min. Then the reaction mixture was heated at100° C. for 16 h. After completion of the reaction (monitored by TLC andLCMS), the reaction mixture was cooled to room temperature, diluted withice cold water and extracted with ethyl acetate (3×). Combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-15% ethyl acetate in n-hexaneto afford 1 g (44% yield) of compound L21-4 as yellow solid.

LCMS-Condition-1: [M+H]⁺=371.35; Rt=2.21 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.95 (s, 1H), 6.88-7.02 (m, 6H), 6.84 (d,J=7.34 Hz, 2H), 6.79 (br. s, 1H), 6.57 (d, J=8.31 Hz, 1H), 6.45 (d,J=8.31 Hz, 1H), 3.68 (s, 3H), 3.52 (t, J=7.09 Hz, 2H), 2.77-2.84 (m,2H), 2.59 (t, J=6.85 Hz, 2H), 2.34-2.45 (m, 2H), 2.09 (s, 3H).

To a solution of2-(4-(6-methoxy-2-(o-tolyl)-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-olL21-4 (800 mg, 2.162 mmol) in DCM (10 mL) was added triethylamine (1.19mL, 8.613 mmol) and tosyl chloride (618 mg, 3.241 mmol) at roomtemperature and stirred for 18 h. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was quenched withwater and extracted with ethyl acetate (3×). Combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-15% ethyl acetate in n-hexane to afford700 mg (63% yield) of compound L21-5 as colourless sticky solid.

LCMS-Condition-1: [M+H₂O]⁺=542.70; Rt=2.49 min

To a solution of4-(6-methoxy-2-(o-tolyl)-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L21-5 (700 mg, 1.334 mmol) in ethyl acetate (30mL) was added 10% palladium on carbon (800 mg) at room temperature undernitrogen atmosphere. The reaction mixture was stirred under hydrogenatmosphere at room temperature for 18 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was filteredthrough a pad of Celite™ and washed with methanol. The filtrate wasconcentrated under reduced pressure to afford 499 mg (70% yield) ofcompound L21-6 as colourless sticky liquid.

LCMS-Condition-1: [M+Na]⁺=549.20; Rt=2.46 min

To a solution of4-(6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L21-6 (200 mg, 0.380 mmol) in acetonitrile (2mL) was added ethyl amine (171 mg, 3.802 mmol) and DIPEA (0.66 mL, 3.802mmol) in a seal tube. The reaction mixture was further stirred at roomtemperature for 3 days. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was diluted with water and extractedwith ethyl acetate (3×). Combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-10% methanol in CH₂Cl₂ to afford 150 mg (99% yield) of compound L21-7as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=400.25; Rt=1.86 min

To a solution ofN-ethyl-2-(4-((1R,2S)-6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amineL21-7 (119 mg, 0.297 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added borontribromide (0.05 mL, 0.595 mmol) drop wise. The reaction mixture wasstirred at the same temperature for 45 min. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was quenchedwith saturated NaHCO₃ solution, and extracted with CH₂Cl₂. The separatedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by preparativeHPLC to afford 20 mg (16% yield) of LA-21 as off white solid.

LCMS-Condition-1: [M+H]⁺=386.20; Rt=1.44 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.14 (br. s, 1H), 7.16 (d, J=7.83 Hz, 1H),7.00 (t, J=7.58 Hz, 1H), 6.80 (d, J=7.82 Hz, 2H), 6.74 (t, J=7.34 Hz,1H), 6.66 (d, J=8.31 Hz, 1H), 6.62 (d, J=1.96 Hz, 1H), 6.49 (dd, J=2.45,8.31 Hz, 1H), 6.25 (d, J=7.82 Hz, 2H), 6.09 (d, J=7.82 Hz, 1H), 4.24 (d,J=4.89 Hz, 1H), 3.46 (dd, J=4.16, 12.47 Hz, 1H), 2.93-3.02 (m, 2H),2.63-2.71 (m, 2H), 2.56 (q, J=6.85 Hz, 4H), 2.44 (s, 3H), 2.10-2.22 (m,2H), 1.61 (d, J=11.25 Hz, 1H), 0.99 (t, J=7.09 Hz, 3H).

(5R,6S)-5-(4-(2-((cyclopropylmethyl)amino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol(LA-22)

To a solution of4-(6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate 21-6 (200 mg, 0.380 mmol) in acetonitrile (2mL) was added cyclopropylmethanamine (269 mg, 3.802 mmol) and DIPEA(0.66 mL, 3.802 mmol) in a sealed tube. The reaction mixture was stirredat room temperature for 3 days. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was diluted with waterand extracted with ethyl acetate (2×). Combined organic layer dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-5% methanol in CH₂Cl₂ to afford 120 mg (74% yield) of compound22-7 as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=426.25; Rt=1.90 min

To a solution ofN-(cyclopropylmethyl)-2-(4-((1R,2S)-6-methoxy-2-(o-tolyl)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amine22-7 (120 mg, 0.281 mmol) in CH₂Cl₂ (12 mL) at 0° C. was added borontribromide (0.08 mL, 0.563 mmol) drop wise. Then the reaction mixturewas stirred at the same temperature for 45 min. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was quenchedwith saturated NaHCO₃ solution, and extracted with CH₂Cl₂ (3×). Theseparated organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bypreparative HPLC to afford 30 mg (24% yield) of LA-22 (TFA salt) as offwhite solid.

LCMS-Condition-1: [M+H]⁺=412.20; Rt=1.71 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (br. s, 1H), 8.47 (br. s, 2H), 7.17(d, J=7.34 Hz, 1H), 7.01 (t, J=7.09 Hz, 1H), 6.85 (d, J=7.82 Hz, 2H),6.76 (t, J=7.34 Hz, 1H), 6.57-6.68 (m, 2H), 6.49 (dd, J=2.69, 8.07 Hz,1H), 6.31 (d, J=7.82 Hz, 2H), 6.09 (d, J=7.82 Hz, 1H), 4.26 (d, J=4.89Hz, 1H), 3.47 (m, 1H), 2.93-3.09 (m, 4H), 2.71-2.83 (m, 4H), 2.45 (s,3H), 2.09-2.21 (m, 1H), 1.59-1.67 (m, 1H), 0.95-1.06 (m, 1H), 0.54-0.61(m, 2H), 0.29-0.35 (m, 2H)

5-(4-(2-(Ethylamino)ethyl)phenyl)-6-(4-isopropylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol(LA-31)

To a solution of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one L31-1 (5 g,28.41 mmol) in xylene (125 mL) was added 1-bromo-4-isopropylbenzene(6.78 g, 34.07 mmol) followed by cesium carbonate (32.4 g, 99.41 mmol)and degassed with argon for 15 min in a sealed tube. To the resultingsolution was added Pd(OAc)₂ (636 mg, 2.839 mmol) and Xanthphos (2.5 g,4.251 mmol) and degassing was continued for another 15 min. Then thereaction mixture was sealed properly and heated to 130° C. for 24 h.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was filtered through a pad of Celite™ and the filtratewas concentrated under reduced pressure. The resulting crude compoundwas purified by silica gel column chromatography eluting with 0-10%ethyl acetate in n-hexane to afford 2.5 g (30% yield) of compound L31-2as brown oil.

LCMS-Condition-1: [M+H]⁺=295.05; Rt=2.22 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.87 (d, J=8.31 Hz, 1H), 7.15-7.20 (m, 2H),7.08 (d, J=8.31 Hz, 2H), 6.89-6.94 (m, 2H), 3.84 (s, 3H), 3.80 (dd,J=4.89, 11.25 Hz, 1H), 3.02-3.13 (m, 1H), 2.82-2.98 (m, 2H), 2.20-2.36(m, 2H), 1.20 (d, J=6.85 Hz, 6H).

To a solution of2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one L31-2(2.5 g, 8.503 mmol) in toluene (50 mL) at 0° C. was added PBr₃ (1.2 mL,12.74 mmol) drop wise. Then the reaction mixture was heated at 100° C.for 16 h. After completion of the reaction (monitored by TLC and LCMS),the reaction mixture was quenched with saturated NaHCO₃ solution andextracted with ethyl acetate (3×). Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-8% ethyl acetate in n-hexane to afford 1.3g (43% yield) of compound L31-3 as off white solid.

LCMS-Condition-1: [M+H]⁺=358.00; Rt=2.71 min

To a stirred solution of cesium carbonate (4.1 g, 12.60 mmol) in water(6 mL) was added solution of4-bromo-3-(4-isopropylphenyl)-7-methoxy-1,2-dihydronaphthalene L31-3(1.5 g, 4.201 mmol) and2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol(1.04 g, 4.201 mmol) in DMF (30 mL) and degassed with argon for 20 minin a seal tube. To the resulting solution was added TPP (0.109 g, 0.416mmol) and palladium acetate (47 mg, 0.210 mmol) at room temperature andpurged with argon for another 15 min. The reaction mixture was thenheated at 100° C. for 16 h. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was concentrated under reducedpressure. The resulting crude compound was purified by silica gel columnchromatography eluting with 0-15% ethyl acetate in n-hexane to afford1.1 g (66% yield) of compound L31-4 as yellow solid.

LCMS-Condition-1: [M+H]⁺=399.20; Rt=2.74 min

To a solution of2-(4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-olL31-4 (1.1 g, 2.760 mmol) in DCM (20 mL) at 0° C. was addedtriethylamine (1.5 mL, 11.04 mmol) followed by tosyl chloride (1.05 g,5.520 mmol). The reaction mixture was then stirred at room temperaturefor 18 h. After completion of the reaction (monitored by TLC and LCMS),the reaction mixture was concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-15% ethyl acetate in n-hexane to afford 1.5 g (98% yield) of compoundL31-5 as colourless sticky solid.

LCMS-Condition-1: [M+Na]⁺=575.30; Rt=2.71 min

To a solution of4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L31-5 (300 mg, 0.542 mmol) in acetonitrile (1mL) was added ethyl amine (146 mg, 3.256 mmol) and DIPEA (1.1 mL, 6.513mmol) in a seal tube. The reaction mixture was then stirred at roomtemperature for 3 days. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-10% methanol in CH₂Cl₂ to afford 200 mg(87% yield) of compound L31-6 as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=426.15; Rt=2.43 min

To a solution ofN-ethyl-2-(4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-amineL31-6 (200 mg, 0.469 mmol) in ethyl acetate:methanol (4:1, 25 mL) wasadded 10% palladium on carbon (500 mg) at room temperature undernitrogen atmosphere. The reaction mixture was then stirred underhydrogen atmosphere at room temperature for 18 h. After completion ofthe reaction (monitored by TLC and LCMS), the reaction mixture wasfiltered through a pad of Celite™ and washed with methanol. The filtratewas concentrated under reduced pressure to afford 170 mg (85% yield) ofcompound L31-7 as colourless sticky solid.

LCMS-Condition-1: [M+H]⁺=428.30; Rt=1.92 min

To a solution ofN-ethyl-2-(4-(2-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amineL31-7 (170 mg, 0.397 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added 1Msolution of boron tribromide in CH₂Cl₂ (0.8 mL, 0.795 mmol) drop wise.Then the reaction mixture was stirred at the same temperature for 45min. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with saturated NaHCO₃ solution, andextracted with CH₂Cl₂ (3×). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by preparative HPLC to afford 25 mg (15%yield) of LA-31 as off white solid.

LCMS-Condition-1: [M+H]⁺=414.40; Rt=1.59 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.20 (br. s, 1H), 7.06 (d, J=8.31 Hz, 2H),6.88 (d, J=7.83 Hz, 2H), 6.78 (d, J=8.31 Hz, 2H), 6.66-6.69 (m, 2H),6.54 (dd, J=2.20, 8.07 Hz, 1H), 6.37 (d, J=7.83 Hz, 2H), 4.25 (d, J=4.89Hz, 1H), 3.32-3.35 (m, 1H), 2.96-3.10 (m, 2H), 2.82-2.91 (m, 3H),2.66-2.79 (m, 4H), 2.00-2.08 (m, 2H), 1.72-1.80 (m, 1H), 1.22 (dd,J=4.40, 6.85 Hz, 6H), 1.11 (t, J=7.09 Hz, 3H).6-(4-Isopropylphenyl)-5-(4-(2-(propylamino)ethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol(LA-32)

To a solution of4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L31-5 (300 mg, 0.542 mmol) in acetonitrile (1mL) was added propyl amine (192 mg, 3.256 mmol) and DIPEA (1.1 mL, 6.513mmol) in a seal tube. The reaction mixture was then stirred at roomtemperature for 3 days. After completion of the reaction (monitored byTLC and LCMS), the reaction mixture was diluted with water and extractedwith ethyl acetate (2×). Combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-10% methanol in CH₂Cl₂ to afford 200 mg (84% yield) of compound L32-6as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=440.55 Rt=1.66 min

To a solution ofN-(4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenethyl)propan-1-amineL32-6 (200 mg, 0.454 mmol) in ethyl acetate:methanol (4:1, 25 mL) wasadded 10% palladium on carbon (500 mg) at room temperature undernitrogen atmosphere. Then the reaction mixture was stirred underhydrogen atmosphere at room temperature for 18 h. After completion ofthe reaction (monitored by TLC and LCMS), the reaction mixture wasfiltered through a pad of Celite™ and washed with methanol. The filtratewas concentrated under reduced pressure to afford 170 mg (85% yield) ofcompound L32-7 as colourless sticky solid.

LCMS-Condition-1: [M+H]⁺=442.25 Rt=1.78 min

To a solution ofN-(4-(2-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenethyl)propan-1-amineL32-7 (170 mg, 0.384 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added 1Msolution of boron tribromide in CH₂Cl₂ (0.77 mL, 0.769 mmol) drop wise.Then the reaction mixture was stirred at the same temperature for 45min. After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with saturated NaHCO₃ solution, andextracted with CH₂Cl₂ (3×). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by preparative HPLC to afford 20 mg (12%yield) of LA-32 as off white solid.

LCMS-Condition-1: [M+H]⁺=428.40; Rt=1.65 min

¹H NMR (400 MHz, CD₃OD) δ: 6.99 (d, J=7.83 Hz, 2H), 6.85 (d, J=8.31 Hz,2H), 6.72 (d, J=7.83 Hz, 2H), 6.66-6.70 (m, 2H), 6.52 (dd, J=2.69, 8.07Hz, 1H), 6.40 (d, J=8.31 Hz, 2H), 4.24 (d, J=4.89 Hz, 1H), 3.34-3.36 (m,1H), 2.99-3.09 (m, 2H), 2.90-2.97 (m, 2H), 2.71-2.79 (m, 4H), 2.14-2.25(m, 1H), 1.74-1.81 (m, 1H), 1.54-1.65 (m, 3H), 1.22 (dd, J=3.42, 6.85Hz, 6H), 0.96 (t, J=7.34 Hz, 3H).5-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenyl)-6-(4-isopropylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol(LA-33)

To a solution of4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenethyl4-methylbenzenesulfonate L31-5 (300 mg, 0.542 mmol) in acetonitrile (1mL) was added cyclopropylmethanamine (231 mg, 3.256 mmol) and DIPEA (1.1mL, 6.513 mmol) in a seal tube. Then the reaction mixture was stirred atroom temperature for 3 days. After completion of the reaction (monitoredby TLC and LCMS), the reaction mixture was diluted with water andextracted with ethyl acetate (2×). Combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by silica gel column chromatography elutingwith 0-10% methanol in CH₂Cl₂ to afford 200 mg (82% yield) of compoundL33-6 as colourless semisolid.

LCMS-Condition-1: [M+H]⁺=452.35; Rt=1.98 min

To a solution ofN-(cyclopropylmethyl)-2-(4-(2-(4-isopropylphenyl)-6-methoxy-3,4-dihydronaphthalen-1-yl)phenyl)ethan-1-amineL33-6 (200 mg, 0.442 mmol) in ethyl acetate:methanol (4:1, 25 mL) wasadded 10% palladium on carbon (500 mg) at room temperature undernitrogen atmosphere. The reaction mixture was stirred under hydrogenatmosphere at room temperature for 18 h. After completion of thereaction (monitored by TLC and LCMS), the reaction mixture was filteredthrough a pad of Celite™ and washed with methanol. The filtrate wasconcentrated under reduced pressure to afford 170 mg (85% yield) ofcompound L33-7 as colourless sticky solid.

LCMS-Condition-1: [M+H]⁺=454.35; Rt=1.98 min

To a solution ofN-(cyclopropylmethyl)-2-(4-(2-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)ethan-1-amineL33-7 (160 mg, 0.352 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added 1Msolution of boron tribromide in CH₂Cl₂ (1.2 mL, 1.237 mmol) drop wise.The reaction mixture was stirred at the same temperature for 45 min.After completion of the reaction (monitored by TLC and LCMS), thereaction mixture was quenched with saturated NaHCO₃ solution, andextracted with CH₂Cl₂ (3×). The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude compound was purified by preparative HPLC to afford 50 mg (32%yield) of LA-33 as off white solid.

LCMS-Condition-1: [M+H]⁺=440.40; Rt=1.65 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.21 (s, 1H), 7.07 (d, J=7.83 Hz, 2H), 6.91(d, J=7.83 Hz, 2H), 6.80 (d, J=8.31 Hz, 2H), 6.67-6.71 (m, 2H), 6.55(dd, J=1.96, 8.31 Hz, 1H), 6.40 (d, J=7.83 Hz, 2H), 4.27 (d, J=4.89 Hz,1H), 3.34-3.36 (m, 1H), 3.00-3.12 (m, 4H), 2.79-2.92 (m, 4H), 1.98-2.10(m, 2H), 1.78 (d, J=5.38 Hz, 1H), 1.23 (dd, J=4.89, 6.85 Hz, 6H),0.96-1.04 (m, 2H), 0.59-0.65 (m, 2H), 0.33-0.39 (m, 2H).

3-(4-(2-(Cyclopropylamino)ethyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol(BT-05)

To 3-methoxybenzenethiol T05-1 (50 g, 357.1 mmol) in acetone (1 Lit) at0° C. was added potassium carbonate (49 g, 357.1 mmol) and2-bromo-1,1-diethoxyethane (70 g, 357.1 mmol). The reaction mixture wasallowed to attain room temperature and stirred for another 16 h. Aftercompletion of the reaction, the reaction mixture was filtered andconcentrated under reduced pressure resulting in the crude residue. Thecrude residue was diluted with water and extracted with CH₂Cl₂ (500 mL×)and the separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford 100 g (crude)of compound T05-2 as colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.28 (t, J=8.31 Hz, 1H), 6.99 (s, 1H), 6.97(d, J=1.47 Hz, 1H), 6.80-6.84 (m, 1H), 4.67 (t, J=5.38 Hz, 1H), 3.81 (s,3H), 3.51-3.71 (m, 4H), 3.20 (d, J=5.38 Hz, 2H), 1.16 (t, J=7.09 Hz, 6H)

To BF₃.Et₂O (24 mL) in CH₂Cl₂ (2000 mL) at 0° C. was added a solution of(2,2-diethoxyethyl)(3-methoxyphenyl)sulfane T05-2 (25 g, 97.65 mmol) inCH₂Cl₂ (200 mL) drop wise. The reaction mixture was allowed to attainroom temperature and stirred for 1 h. After completion of the reaction,the reaction mixture was quenched with saturated NaHCO₃ solution andextracted with CH₂Cl₂. The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-5% CH₂Cl₂ in n-hexane to afford 8 g (50%yield) of compound T05-4 as colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.74 (d, J=8.80 Hz, 1H), 7.55 (d, J=2.45Hz, 1H), 7.51 (d, J=5.38 Hz, 1H), 7.32 (d, J=5.38 Hz, 1H), 6.99 (dd,J=2.45, 8.80 Hz, 1H), 3.80 (s, 3H).

To 6-methoxybenzo[b]thiophene T05-3 (1.3 g, 7.926 mmol) in DCE (30 mL)was added p-TSA (15 mg, 0.079 mmol) and stirred for 10 min at roomtemperature. Followed by addition of NBS (1.41 g, 7.926 mmol) at 0° C.portion wise and stirred at room temperature for 1 h. After completionof the reaction, the reaction mixture was quenched with saturatedNa₂S203/NaHCO₃ solution and extracted with CH₂Cl₂. The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting crude compound was purified by silicagel column chromatography eluting with 0-6% CH₂Cl₂ in n-hexane to afford1.3 g (68% yield) of compound T05-4 as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.67 (d, J=8.80 Hz, 1H), 7.54 (d, J=2.45Hz, 1H), 7.51 (s, 1H), 6.99 (dd, J=2.45, 8.80 Hz, 1H), 3.80 (s, 3H).

To 2-bromo-6-methoxybenzo[b]thiophene T05-4 (1 g, 4.149 mmol) ando-tolylboronic acid 5 (677 mg, 4.979 mmol) in ethanol:H₂O:Toluene(20:10:20 mL) was added Na₂CO₃ (1.75 g, 16.59 mmol) and purged withargon for 15 min. Followed by addition oftetrakis(triphenylphosphine)palladium(0) (230 mg, 0.207 mmol) and purgedwith argon for another 10 min. The reaction mixture was further heatedto reflux for 16 h. After completion of the reaction, the reactionmixture was quenched with ice cold water and extracted with ethylacetate (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-12% CH₂Cl₂ in n-hexane to afford 1 g (95% yield) of compoundT05-6 as colourless oil.

LCMS-Condition-1: [M+H]⁺=254.95; Rt=2.40 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.75 (d, J=8.80 Hz, 1H), 7.56 (s, 1H),7.43-7.47 (m, 1H), 7.39 (s, 1H), 7.27-7.37 (m, 3H), 7.02 (dd, J=2.45,8.80 Hz, 1H), 3.83 (s, 3H), 2.45 (s, 3H).

To 6-methoxy-2-(o-tolyl)benzo[b]thiophene T05-6 (400 mg, 1.574 mmol) inCHCl₃ (40 mL) at 0° C. was added bromine (0.06 mL, 2.362 mmol) drop wiseover a period of 30 min. After completion of the reaction, the reactionmixture was quenched with saturated Na₂S203 solution and extracted withCH₂Cl₂ (3×). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The resulting crudecompound was purified by silica gel column chromatography eluting with0-10% CH₂Cl₂ in n-hexane to afford 400 mg (76% yield) of compound T05-7as off white solid.

LCMS-Condition-1: [M+H]⁺=333.70; Rt=2.45 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.58-7.62 (m, 2H), 7.22-7.37 (m, 4H),7.08-7.13 (m, 1H), 3.80 (s, 3H), 2.15 (s, 3H)

To 3-bromo-6-methoxy-2-(o-tolyl)benzo[b]thiophene T05-7 (400 mg, 1.146mmol) in CH₂Cl₂ (mL) was added TFA (mL, mmol) and 30% H₂O₂ (mL, mmol) atroom temperature and stirred for 2 h. After completion of the reaction,the reaction mixture was quenched with saturated NaHCO₃ solution, andextracted with CH₂Cl₂. The separated organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford 650 mg (crude) of the title compound T05-8 as off white solidwhich was used as such for the next step without further purification.

LCMS-Condition-1: [M+H]⁺=348.80; Rt=2.00 min

To 3-bromo-6-methoxy-2-(o-tolyl)benzo[b]thiophene 1-oxide T05-8 (2.5 g,7.143 mmol) in DMF (40 mL) was added CuI (555 mg, 2.915 mmol), cesiumcarbonate (950 mg, 2.915 mmol) followed by 4-(2-hydroxyethyl)phenol (2g, 14.49 mmol) at room temperature. The reaction mixture was furtherheated at 100° C. for 7 h. After completion of the reaction, thereaction mixture was quenched with ice cold water and extracted withethyl acetate. The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-80% ethyl acetate in n-hexane to afford 2.2 g (38% yield) ofcompound T05-9 as pale yellow oil.

LCMS-Condition 02: [M+H]⁺=407.15; Rt=1.86 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.95 (s, 1H), 7.75 (d, J=2.20 Hz, 1H), 7.28(d, J=7.46 Hz, 1H), 7.13-7.23 (m, 4H), 7.01-7.04 (m, 2H), 6.94-6.98 (m,2H), 4.58 (t, J=5.14 Hz, 1H), 3.88 (s, 3H), 3.43-3.49 (m, 2H), 2.89 (s,3H), 2.58 (t, J=7.15 Hz, 2H)

To 3-(4-(2-hydroxyethyl)phenoxy)-6-methoxy-2-(o-tolyl)benzo[b]thiophene1-oxide T05-9 (500 mg, 1.231 mmol) in DCM (10 mL) was addedtriethylamine (0.5 mL, 0.369 mmol) and stirred for 10 min, followed bythe addition of tosyl chloride (235 mg, 1.231 mmol) in two portions atroom temperature and stirred for another 16 h. After completion of thereaction, the reaction mixture was diluted with water and extracted withethyl acetate (3×). Separated organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudecompound was purified by silica gel column chromatography eluting with0-80% ethyl acetate in n-hexane to afford 410 mg (59% yield) of compoundT05-10 as pale yellow oil.

LCMS-Condition 02: [M+H]⁺=561.20; Rt=2.17 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.76 (d, J=1.96 Hz, 1H), 7.66 (d, J=8.31Hz, 2H), 7.38 (d, J=8.80 Hz, 2H), 7.27 (d, J=6.36 Hz, 1H), 7.21-7.24 (m,1H), 7.14-7.18 (m, 4H), 6.94-6.96 (m, 4H), 4.05-4.09 (m, 2H), 3.88 (s,3H), 2.75 (t, J=6.36 Hz, 2H), 2.38 (s, 3H), 2.26 (s, 3H).

To 4-((6-methoxy-1-oxido-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)phenethyl4-methylbenzenesulfonate T05-10 (350 mg, 0.624 mmol) in acetonitrile (5mL) was added cyclopropanamine (356 mg, 6.242 mmol) and DIPEA (0.32 mL,1.872 mmol) in a seal tube. The reaction mixture was stirred at roomtemperature for 48 h. After completion of the reaction, the reactionmixture was diluted with water and extracted with ethyl acetate (2×).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-5% methanol in CH₂Cl₂ toafford 100 mg (99% yield) of compound T05-11 as colourless oil.

LCMS-Condition 02: [M+H]⁺=446.15; Rt=2.07 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.75 (d, J=1.96 Hz, 1H), 7.27-7.30 (m, 1H),7.25 (d, J=7.34 Hz, 1H), 7.11-7.20 (m, 4H), 6.98 (d, J=3.42 Hz, 4H),4.09 (d, J=4.89 Hz, 1H), 3.89 (s, 3H), 3.17 (d, J=4.40 Hz, 1H),2.64-2.70 (m, 2H), 2.55 (t, J=7.09 Hz, 2H), 2.26 (s, 3H), 2.05 (tt,J=3.48, 6.54 Hz, 2H), 1.88-1.92 (m, 2H).

To3-(4-(2-(cyclopropylamino)ethyl)phenoxy)-6-methoxy-2-(o-tolyl)benzo[b]thiophene1-oxide T05-11 (150 mg, 0.336 mmol) in THE (10 mL) at 0° C. was addedLAH (64 mg, 1.684 mmol) portion wise. The reaction mixture was allowedto attain room temperature and stirred for 2 h. After completion of thereaction, the reaction mixture was quenched with saturated Na₂SO₄solution, filtered through a pad of Celite™ and washed with 15% methanolin CH₂Cl₂. The filtrate was concentrated under reduced pressure and thecrude compound was purified by silica gel column chromatography elutingwith 0-5% methanol in CH₂Cl₂ to afford 120 mg (83% yield) of compoundT05-12 as colourless oil.

LCMS-Condition 01: [M+H]⁺=430.15; Rt=2.74 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.62 (d, J=2.20 Hz, 1H), 7.36 (d, J=7.46Hz, 1H), 7.27-7.30 (m, 2H), 7.24 (s, 1H), 7.19-7.22 (m, 1H), 7.05 (d,J=8.56 Hz, 2H), 6.99 (dd, J=2.26, 8.74 Hz, 1H), 6.77 (d, J=8.56 Hz, 2H),3.84 (s, 3H), 2.70 (d, J=7.70 Hz, 2H), 2.55-2.61 (m, 2H), 2.33 (s, 3H),2.04 (tt, J=3.52, 6.63 Hz, 2H), 0.30-0.36 (m, 2H), 0.14-0.19 (m, 2H).

ToN-(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)phenethyl)cyclopropanamineT05-12 (120 mg, 0.279 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added solutionof boron tribromide (0.13 mL, 1.389 mmol) in CH₂Cl₂ (1 mL) drop wise.The reaction mixture was allowed to attain room temperature and stirredfor 3 h. After completion of the reaction, the reaction mixture wasquenched with saturated NaHCO₃ solution, and extracted with CH₂Cl₂. Theseparated organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-5% methanol in CH₂Cl₂ toafford 33 mg (29% yield) of BT-05 as off white solid.

LCMS-Condition-1: [M+H]⁺=416.10; Rt=1.52 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.80 (s, 1H), 7.29-7.36 (m, 2H), 7.25-7.28(m, 2H), 7.14-7.19 (m, 2H), 7.04 (d, J=8.44 Hz, 2H), 6.84 (dd, J=1.96,8.68 Hz, 1H), 6.76 (d, J=8.44 Hz, 2H), 2.71-2.77 (m, 2H), 2.57-2.62 (m,2H), 2.31 (s, 3H), 2.08-2.11 (m, 1H), 0.35 (d, J=4.52 Hz, 2H), 0.19-0.24(m, 2H).

3-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol(BT-12)

To a solution of4-((6-methoxy-1-oxido-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)phenethyl4-methylbenzenesulfonate T05-10 (400 mg, 0.713 mmol) in acetonitrile (20mL) was added cyclopropylmethanamine (506 mg, 7.114 mmol) and DIPEA(0.62 mL, 3.565 mmol). The reaction mixture was stirred at roomtemperature for 48 h in sealed tube. After completion of the reaction(monitored by TLC and LCMS), the reaction mixture was diluted with waterand extracted with ethyl acetate (2×). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-5% methanol in CH₂Cl₂ to afford 210 mg(64% yield) of compound T12-11 as colourless oil.

LCMS-Condition 02: [M+H]⁺=460.20; Rt=2.23 min

To a solution of3-(4-(2-((cyclopropylmethyl)amino)ethyl)phenoxy)-6-methoxy-2-(o-tolyl)benzo[b]thiophene1-oxide T12-11 (200 mg, 0.435 mmol) in THF (3 mL) at 0° C. was added LAH(50 mg, 1.316 mmol) portion wise. The reaction mixture was allowed toattain room temperature and stirred for another 16 h. After completionof the reaction (monitored by TLC and LCMS), the reaction mixture wascooled to 0° C. and quenched with saturated Na₂SO₄ solution (2 mL). Theresulting solution was filtered through a pad of Celite™ and washed with15% methanol in CH₂Cl₂. The filtrate was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 150 mg (78% yield) ofcompound T12-12 as pale yellow oil.

LCMS-Condition 01: [M+H]⁺=444.11; Rt=1.75 min

To a solution ofN-(cyclopropylmethyl)-2-(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)phenyl)ethan-1-amineT12-12 (150 mg, 0.338 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added borontribromide (0.09 mL, 1.012 mmol) drop wise. The reaction mixture wasallowed to attain room temperature and stirred for 4 h. After completionof the reaction (monitored by TLC and LCMS), the reaction mixture wasquenched with saturated NaHCO₃ solution, and extracted with 15% methanolin CH₂Cl₂. The separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-8% methanolin CH₂Cl₂ to afford 23 mg (17% yield) of BT-12 as off white solid.

LCMS-Condition-1: [M+H]⁺=430.10; Rt=1.53 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 8.54-8.60 (m, 1H), 7.31-7.36(m, 2H), 7.25-7.29 (m, 2H), 7.18-7.22 (m, 1H), 7.15 (d, J=8.80 Hz, 1H),7.11 (d, J=8.31 Hz, 2H), 6.80-6.86 (m, 3H), 3.03-3.09 (m, 2H), 2.76-2.85(m, 4H), 2.32 (s, 3H), 0.97-1.04 (m, 1H), 0.53-0.59 (m, 2H), 0.29-0.34(m, 2H)

3-(4-((1-Propylazetidin-3-ylidene)methyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol(BT-17)

To a mixture of 3-bromo-6-methoxy-2-(o-tolyl)benzo[b]thiophene 1-oxideT17-1 (5.77 g, 16.53 mmol) and 4-hydroxybenzaldehyde (4 g, 32.78 mmol)in DMF (40 mL) was added cesium carbonate (32.1 g, 98.46 mmol) at roomtemperature in a sealed tube. The reaction mixture was heated at 100° C.for 3 h. After completion of the reaction, the reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting crude compound waspurified by silica gel column chromatography eluting with 0-40% ethylacetate in n-hexane to afford 5.3 g (82% yield) of compound T17-2 aslight yellow solid.

LCMS-Condition 01: [M+H]⁺=391.30; Rt=1.89 min

To4-((6-methoxy-1-oxido-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)benzaldehydeT17-2 (2 g, 5.122 mmol) in THE (40 mL) at 0° C. was added lithiumaluminium hydride (583 mg, 15.36 mmol) portion wise. The reactionmixture was stirred at room temperature for 2 h. After completion of thereaction, the reaction mixture was quenched with saturated Na₂SO₄solution, and extracted with ethyl acetate. The separated organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-15% methanol in CH₂Cl₂ to afford 1.9 g(98% yield) of compound T17-3 as pale yellow oil.

LCMS-Condition 01: [M+18]=393.10; Rt=2.24 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.62 (d, J=1.96 Hz, 1H), 7.36 (d, J=7.82Hz, 1H), 7.26-7.30 (m, 2H), 7.22 (d, J=8.80 Hz, 2H), 7.16 (d, J=8.80 Hz,2H), 6.99 (d, J=1.96 Hz, 1H), 6.81 (d, J=8.31 Hz, 2H), 5.04 (t, J=5.62Hz, 1H), 4.36 (d, J=5.87 Hz, 2H), 3.83 (s, 3H), 2.33 (s, 3H).

To a solution of(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)phenyl)methanolT17-3 (1.9 g, 5.046 mmol) in CH₂Cl₂ (20 mL) was added PBr₃ (1.36 g,5.024 mmol) at 0° C. drop wise and stirred at room temperature for 2 h.After completion of the reaction, the reaction mixture was quenched withsaturated NaHCO₃ solution and extracted with CH₂Cl₂. The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to afford 2.1 g (95% yield) of compound T17-4 aspale yellow oil.

LCMS-Condition 01: [M+H]⁺=440.05; Rt=2.47 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.63 (d, J=1.96 Hz, 1H), 7.35 (d, J=7.34Hz, 1H), 7.26-7.32 (m, 4H), 7.24 (d, J=8.80 Hz, 2H), 7.00 (dd, J=1.96,8.80 Hz, 1H), 6.83 (d, J=8.80 Hz, 2H), 4.63 (s, 2H), 3.84 (s, 3H), 2.32(s, 3H).

To 3-(4-(bromomethyl)phenoxy)-6-methoxy-2-(o-tolyl)benzo[b]thiopheneT17-4 (2 g, 4.558 mmol) in benzene (30 mL) was added triphenyl phosphine(1.8 g, 6.824 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (1.17 g,6.842 mmol) at room temperature and stirred for 4 h. The reactionmixture was concentrated under reduced pressure and the crudeintermediate was washed with n-hexane and dried. The crude intermediatewas dissolved in CH₂Cl₂ (20 mL) and potassium tert-butoxide (1.53 g,13.66 mmol) and solution of tert-butyl 3-oxoazetidine-1-carboxylate(1.17 g, 6.842 mmol) in CH₂Cl₂ (10 mL) at room temperature and stirredfor 16 h. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure, diluted with water and extractedwith CH₂Cl₂ (3×). The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude compound was purified by silica gel column chromatography elutingwith 0-20% ethyl acetate in n-hexane to afford 900 mg (39% yield) ofcompound T17-5 as off white solid.

LCMS-Condition-1: [M-^(t)Bu]⁺=458.40; Rt=2.57 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.63 (d, J=2.45 Hz, 1H), 7.35 (d, J=7.34Hz, 1H), 7.26-7.31 (m, 2H), 7.24 (d, J=8.80 Hz, 1H), 7.17-7.22 (m, 1H),7.03 (d, J=8.80 Hz, 2H), 6.99 (dd, J=1.96, 8.80 Hz, 1H), 6.83 (d, J=8.80Hz, 2H), 6.22 (br. s, 1H), 4.69 (br. s, 2H), 4.52 (br. s, 2H), 3.84 (s,3H), 2.32 (s, 3H), 1.39 (s, 9H).

A solution of tert-butyl3-(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)benzylidene)azetidine-1-carboxylateT17-5 (832 mg, 1.619 mmol) in 4M HCl in dioxane (3 mL) was stirred atroom temperature for 2 h. After completion of the reaction, the reactionmixture was quenched with saturated NaHCO₃ solution and extracted with10% methanol in CH₂Cl₂. The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford 810 mg (crude) of compound T17-6 as pale yellow oil which wasused in the next step without further purification.

LCMS-Condition 01: [M+H]⁺=414.15; Rt=1.61 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.28 (br. s, 1H), 7.61-7.66 (m, 1H), 7.35(d, J=7.34 Hz, 1H), 7.28-7.30 (m, 2H), 7.18-7.26 (m, 2H), 7.06 (d,J=8.80 Hz, 2H), 7.00 (dd, J=1.96, 8.80 Hz, 1H), 6.85 (d, J=8.31 Hz, 2H),3.84 (s, 3H), 3.34 (s, 4H), 2.33 (s, 3H).

To3-(4-((6-methoxy-2-(o-tolyl)benzo[b]thiophen-3-yl)oxy)benzylidene)-1-propylazetidineT17-7 (200 mg, 0.438 mmol) in DMF (4 mL) was added sodium methanethiolate (61.5 mg, 0.878 mmol) at room temperature in a microwave vial.The vial was sealed properly and irradiated in microwave at 150° C. for1 h. After completion of the reaction, the reaction mixture was quenchedwith saturated NaHCO₃ solution, and extracted with 15% methanol inCH₂Cl₂. The separated organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude compound waspurified by silica gel column chromatography eluting with 0-5% methanolin CH₂Cl₂ to afford 35 mg (18% yield) of BT-17 as white solid.

LCMS-Condition-1: [M+H]⁺=442.15; Rt=1.55 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.81 (br. s, 1H), 7.29-7.35 (m, 2H),7.22-7.28 (m, 2H), 7.17-7.20 (m, 1H), 7.15 (d, J=8.53 Hz, 1H), 6.97 (d,J=8.78 Hz, 2H), 6.84 (dd, J=2.13, 8.66 Hz, 1H), 6.80 (d, J=8.78 Hz, 2H),6.08-6.13 (m, 1H), 4.17 (br. s, 2H), 4.01 (br. s, 2H), 2.58 (t, J=6.90Hz, 2H), 2.31 (s, 3H), 1.33-1.37 (m, 2H), 0.85 (t, J=7.40 Hz, 3H).

5-(4-(2-(Cyclopropylamino)ethyl)benzyl)-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-8-ol(BX-06)

To a mixture of 3-methoxyphenol (10 g, 80.64 mmol) and ethyl4-bromobutanoate (23.6 g, 120.96 mmol) in acetone (400 mL) was addedpotassium carbonate (33.4 g, 241.93 mmol) at room temperature. Then thereaction mixture was heated to reflux for 18 h. After completion of thereaction (monitored by TLC), the reaction mixture was filtered andwashed with acetone. The filtrate was concentrated under reducedpressure to afford 18 g (94% yield) of compound X6-2 as colourless oil.

LCMS-Condition-01: [M+1]⁺=239.07; Rt=1.96 min

¹H NMR (400 MHz, CDCl₃) δ: 7.17 (t, J=8.31 Hz, 1H), 6.44-6.53 (m, 3H),4.15 (q, J=7.17 Hz, 2H), 3.99 (t, J=6.11 Hz, 2H), 3.78 (s, 3H),2.46-2.54 (m, 2H), 2.04-2.15 (m, 2H), 1.21-1.30 (m, 3H).

To a solution of ethyl 4-(3-methoxyphenoxy)butanoate X6-2 (18 g, 75.63mmol) in THF-MeOH (7:10, 170 mL) was added a solution of lithiumhydroxide (6.3 g, 151.26 mmol) in water (70 mL) at room temperature andstirred for 1 h. After completion of the reaction, the reaction mixturewas concentrated, acidified with 1N HCl solution up to pH=2 andextracted with ethyl acetate (3×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to afford 13 g (82% yield) of compound X6-3 as colourless oil.

LCMS-Condition-01: [M+1]⁺=210.97; Rt=1.64 min

¹H NMR (400 MHz, DMSO-d₆) δ:12.09 (br. s, 1H), 7.14 (t, J=8.07 Hz, 1H),6.49 (d, J=2.45 Hz, 1H), 6.45-6.48 (m, 2H), 3.94 (t, J=6.36 Hz, 2H),3.71 (s, 3H), 2.36 (t, J=7.34 Hz, 2H), 1.85-1.95 (m, 2H).

A solution of 4-(3-methoxyphenoxy)butanoic acid X6-3 (13 g, 61.90 mmol)in Eaton's reagent (75 mL) in a sealed tube was heated at 80° C. for 30min. After completion of the reaction, the reaction mixture was quenchedwith ice cold water and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-20% ethyl acetate inn-hexane to afford 6 g (50% yield) of compound X6-4 as off white solid.

LCMS-Condition-1: [M+1]⁺=193.00; Rt=1.64 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.61 (d, J=8.80 Hz, 1H), 6.72 (dd, J=2.45,8.80 Hz, 1H), 6.64 (d, J=2.45 Hz, 1H), 4.20 (t, J=6.60 Hz, 2H), 3.80 (s,3H), 2.73 (t, J=6.85 Hz, 2H), 2.10 (quin, J=6.72 Hz, 2H).

To a solution of 8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one X6-4 (6g, 31.21 mmol) in xylene (100 mL) was added cesium carbonate (30 g,93.64 mmol) and degassed with argon for 15 min in a sealed tube. To theresulting solution was added 2-bromo toluene (8 g, 46.82 mmol), Pd(OAc)₂(348 mg, 15.60 mmol) and X-phos (1.4 g, 31.21 mmol) and degassing wascontinued for another 5 min at room temperature. Then the reactionmixture was sealed properly and heated at 130° C. for 24 h. Aftercompletion of the reaction, the reaction mixture was filtered through apad of Celite and the filtrate was diluted with ice water and extractedwith ethyl acetate (3×30 mL). The combined organic layer dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-15% ethyl acetate in n-hexane to afford2.5 g (32% yield) of compound X6-5 as yellow solid.

LCMS-Condition-1: [M+H]⁺=283.08; Rt=2.12 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.56 (d, J=8.80 Hz, 1H), 7.29 (d, J=7.34Hz, 1H), 7.17-7.21 (m, 1H), 7.16 (d, J=3.91 Hz, 2H), 6.73 (dd, J=2.20,8.56 Hz, 1H), 6.70 (d, J=2.45 Hz, 1H), 4.62-4.67 (m, 1H), 4.43 (dd,J=6.85, 11.25 Hz, 1H), 3.97-4.08 (m, 1H), 3.83 (s, 3H), 2.39-2.48 (m,2H), 2.05 (s, 3H).

To 150 mL two neck round bottomed flask was added freshly activatedmagnesium turnings (2.7 g, 113.47 mmol) and catalytic amount of iodine.To that (4-(bromomethyl)phenethoxy)(tert-butyl)dimethylsilane C (9.3 g,28.36 mmol) in THE (40 mL) was added and heated at 70° C. for 15 min.After de-colorization of iodine, the reaction mixture was cooled to roomtemperature to 0° C. and a solution of8-methoxy-4-(o-tolyl)-3,4-dihydrobenzo[b]oxepin-5(2H)-one X6-5 (4 g,14.18 mmol) in THE (3 mL) was added and stirred for 3 h at roomtemperature. After completion of the reaction, the reaction mixture wasquenched with saturated ammonium chloride solution and extracted withethyl acetate (3×100 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting crude compound was purified by silica gel columnchromatography eluting with 0-15% ethyl acetate in n-hexane to afford 1g (13% yield) of compound X6-6 as colorless liquid.

LCMS-Condition-1: [M+Na]⁺=555.18; Rt=2.85 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.10 (d, J=8.44 Hz, 2H), 6.96 (d, J=7.46Hz, 2H), 6.85 (d, J=7.95 Hz, 2H), 6.79 (d, J=6.85 Hz, 2H), 6.70 (d,J=7.70 Hz, 1H), 6.59 (d, J=2.57 Hz, 1H), 6.51-6.57 (m, 1H), 4.57 (s,1H), 4.20-4.27 (m, 1H), 3.76 (s, 3H), 3.70-3.74 (m, 4H), 3.59-3.65 (m,1H), 3.47 (d, J=13.45 Hz, 1H), 3.11 (d, J=13.33 Hz, 1H), 2.66 (t, J=6.72Hz, 2H), 2.23 (s, 3H), 1.55-1.59 (m, 1H), 0.84 (s, 9H), −0.05 (s, 6H).

To a boiling solution of5-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzyl)-8-methoxy-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-olX6-6 (700 mg, 1.313 mmol) in ACN (14 mL) was added conc. HCl (0.5 mL) inACN (1 mL) dropwise and continued stirring for 40 min. After completionof the reaction, the reaction mixture was concentrated under reducedpressure. The crude residue was dissolved in ethyl acetate and washedwith saturated NaHCO₃ solution. The separated organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The resulting crude compound was purified by silica gel columnchromatography eluting with 0-60% ethyl acetate in n-hexane to afford350 mg (80% yield) of the title compound X6-7 as white solid.

LCMS-Condition-1: [M+H]⁺=401.05; Rt=2.23 min

¹H NMR (400 MHz, CDCl₃) δ: 7.16-7.23 (m, 3H), 7.11-7.15 (m, 1H), 7.00(d, J=1.96 Hz, 4H), 6.87-6.96 (m, 1H), 6.63-6.65 (m, 1H), 6.60-6.63 (m,1H), 4.66 (td, J=5.14, 10.27 Hz, 1H), 4.58 (ddd, J=4.40, 5.62, 10.03 Hz,1H), 3.79-3.81 (m, 2H), 3.78 (s, 3H), 3.56-3.71 (m, 2H), 2.75 (t, J=6.60Hz, 2H), 2.68 (dt, J=5.14, 9.66 Hz, 1H), 2.29 (t, J=4.40 Hz, 1H), 2.25(s, 3H).

To a solution of2-(4-((8-methoxy-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-5-yl)methyl)phenyl)ethan-1-olX6-7 (400 mg, 0.998 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added triethylamine (0.34 mL, 2.496 mmol) followed by tosyl chloride (285 mg, 1.498mmol). Then the reaction mixture was stirred at room temperature for 18h. After completion of the reaction, the reaction mixture was quenchedwith ice water and extracted with CH₂Cl₂ (3×30 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-20% ethyl acetate in n-hexane to afford380 mg (68% yield) of compound X6-8 as colorless liquid.

LCMS-Condition-1: [M+H]⁺=555.10; Rt=2.47 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.60 (d, J=7.82 Hz, 2H), 7.25-7.34 (m, 4H),7.15-7.22 (m, 3H), 6.87-6.96 (m, 4H), 6.60-6.65 (m, 2H), 4.62 (dt,J=4.65, 10.64 Hz, 2H), 4.52 (dd, J=4.65, 9.54 Hz, 2H), 4.10-4.16 (m,2H), 3.71 (s, 3H), 3.37-3.44 (m, 2H), 2.74 (t, J=6.60 Hz, 2H), 2.36 (s,3H), 2.22 (s, 3H).

To a solution of4-((8-methoxy-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-5-yl)methyl)phenethyl-4-methylbenzenesulfonateX6-8 (350 mg, 0.630 mmol) in acetonitrile (2 mL) was added DIPEA (0.85mL, 6.300 mmol) and cyclopropyl amine (359 mg, 6.300 mmol) at roomtemperature in a sealed tube. Then the reaction mixture was stirred atroom temperature for 3 days. After completion of the reaction, thereaction mixture was concentrated under reduced pressure, diluted withwater and extracted with ethyl acetate (2×15 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel columnchromatography eluting with 0-2% methanol in CH₂Cl₂ to afford 150 mg(54% yield) of compound X6-9 as colorless liquid.

LCMS-Condition-1: [M+H]⁺=440.20; Rt=1.64 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.21 (d, J=8.31 Hz, 1H), 7.17 (d, J=8.31Hz, 1H), 7.07-7.14 (m, 3H), 6.85-6.88 (m, 4H), 6.55 (dd, J=2.69, 8.56Hz, 1H), 6.52 (d, J=2.45 Hz, 1H), 4.48-4.67 (m, 2H), 3.71 (s, 3H), 3.68(d, J=16.00 Hz, 1H), 3.38 (d, J=16.00 Hz, 1H), 2.61-2.69 (m, 2H),2.52-2.58 (m, 3H), 2.13 (s, 3H), 1.93 (td, J=3.06, 6.60 Hz, 2H),0.72-0.81 (m, 2H), 0.19-0.24 (m, 2H).

To a solution ofN-(4-((8-methoxy-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-5-yl)methyl)phenethyl)cyclopropanamineX6-9 (100 mg, 0.227 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added borontribromide (0.02 mL, 0.227 mmol) dropwise. Then the reaction mixture wasstirred at the same temperature for 20 min. After completion of thereaction, the reaction mixture was quenched with saturated NaHCO₃solution, and extracted with CH₂Cl₂. The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by silica gel columnchromatography eluting with 0-5% methanol in CH₂Cl₂ to afford 25 mg (21%yield) of BX-06 as off white solid.

LCMS-Condition-1: [M+H]⁺=426.20; Rt=1.59 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.50 (s, 1H), 7.25-7.30 (m, 1H), 7.15-7.22(m, 4H), 6.95-7.01 (m, 4H), 6.48 (dd, J=2.45, 8.31 Hz, 1H), 6.44 (d,J=2.45 Hz, 1H), 4.51-4.57 (m, 1H), 4.40-4.48 (m, 1H), 3.62 (d, J=16 Hz,1H), 3.34 (d, J=16 Hz, 1H), 2.63-2.70 (m, 3H), 2.51-2.58 (m, 3H), 2.19(s, 3H), 2.19 (t, J=3.91 Hz, 1H), 2.07 (tt, J=3.48, 6.54 Hz, 1H),0.31-0.38 (m, 2H), 0.16-0.23 (m, 2H).

5-(4-(2-(Ethylamino)ethyl)benzyl)-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-8-ol(BX-07)

To a solution of4-((8-methoxy-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-5-yl)methyl)phenethyl4-methylbenzenesulfonate X6-8 (300 mg, 0.542 mmol) in acetonitrile (2mL) was added DIPEA (0.75 mL, 4.32 mmol) and cyclopropyl amine (2M inMeOH, 2.7 mL, 5.42 mmol) at room temperature. Then the reaction mixturewas stirred at room temperature for 72 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure,and diluted with water, extracted with ethyl acetate (2×15 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bysilica gel column chromatography eluting with 0-10% methanol in CH₂Cl₂to afford 150 mg (65% yield) of compound X7-9 as sticky solid.

LCMS-Condition-1: [M+H]⁺=428.55; Rt=1.62 min

¹H NMR (400 MHz, DMSO-d₆) δ: 7.46 (d, J=9.2 Hz, 2H), 7.17-7.31 (m, 5H),7.09 (d, J=7.6 Hz, 2H), 6.61-6.63 (m, 2H), 4.49-4.62 (m, 2H), 3.73 (d,J=15.65 Hz, 1H), 3.71 (s, 3H), 3.39 (d, J=16.14 Hz, 1H), 2.95-3.00 (m,2H), 2.82-2.88 (m, 3H), 2.71 (t, J=8.4 Hz, 2H), 2.40-2.42 (m, 1H), 2.28(s, 3H), 2.18 (br. s, 1H), 1.11 (t, J=7.2 Hz, 3H).

ToN-ethyl-2-(4-((8-methoxy-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-5-yl)methyl)phenyl)ethan-1-amineX7-9 (150 mg, 0.351 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added borontribromide (0.06 mL, 0.702 mmol) dropwise. Then the reaction mixture wasstirred at same the temperature for 30 min. After completion of thereaction, the reaction mixture was quenched with saturated NaHCO₃solution, and extracted with CH₂Cl₂. The separated organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude compound was purified by preparative HPLC to afford10 mg (7% yield) of BX-07 as off white solid.

LCMS-Condition-1: [M+H]⁺=414.50; Rt=1.49 min

¹H NMR (400 MHz, DMSO-d₆) δ: 9.57 (br. s, 1H), 7.26 (d, J=6.36 Hz, 1H),7.12-7.21 (m, 4H), 6.94-7.07 (m, 4H), 6.46 (d, J=8.31 Hz, 1H), 6.42 (s,1H), 4.52-4.61 (m, 1H), 4.42-4.49 (m, 1H), 3.69 (d, J=15.65 Hz, 1H),3.39 (d, J=16.14 Hz, 1H), 2.94-3.01 (m, 2H), 2.80-2.90 (m, 2H),2.68-2.76 (m, 2H), 2.53-2.62 (m, 1H), 2.21 (s, 3H), 2.16 (br. s, 1H),1.23 (br. s, 1H), 1.11 (t, J=7.09 Hz, 3H).

Activity Discussion and Biological Data

In order to demonstrate the utility of the compounds of this invention,an estrogen receptor binding assay was performed wherein many of thecompounds of this invention were shown to demonstrate significantaffinity for the estrogen receptor. Selected compound examples wereassessed for their ability to inhibit estradiol (E2)-inducedproliferation and signaling and for their ability to degrade theestrogen receptor (ER) in breast cancer cells. Furthermore, the abilityof selected compounds to inhibit E2-induced increase in uterine weightin immature rats was assessed by oral dosing. Selected compounds couldbe evaluated in an MCF-7 in vivo xenograft model of breast cancer.

Proliferation Assay in MCF-7 and T47D Cells

MCF-7 and T47D cells were stripped for 3 days in phenol red-freeRPMI1640 media containing 10% charcoal-stripped fetal bovine serum(CS-FBS) and 1% Penicillin/streptomycin (P/S). Cells (volume of 90μl/well) were seeded in 96 well plates at a density of 2500 cells/wellfor MCF-7 cells and 1500 cells/well for T47D cells. On the followingday, plates were treated with the test compounds (10× concentration inmedia, volume of 10p/well added) both in the absence and in the presenceof two doses of E2 (10 pM and 1 nM). The cells were incubated with testcompounds for 7 days. The viability of the cells was assessed usingCellTiterGlo (Promega, Cat #G7573) according to the manufacturer'sinstructions. Growth inhibition curves and IC₅₀ values were calculatedusing the GraphPadPrism 6.0 software. Data values shown in Table 1 wereobtained using the 10 pM dose of E2.

Quantitative PCR (qPCR) to Assess ER Signaling in MCF-7 Cells

MCF-7 cells were stripped for 3 days in phenol red-free RPMI1640 mediacontaining 10% charcoal-stripped fetal bovine serum (CS-FBS) and 1%Penicillin/streptomycin (P/S). Cells (volume of 90 μl/well) were seededin 96 well plates at a density of 20000 cells/well. On the followingday, plates were treated with the test compounds (10× concentration inmedia, volume of 10 μl/well added) both in the absence and in thepresence of E2 (1 nM). The cells were incubated with test compounds for24 h. Cell lysates were prepared using the Cells-to-CT kit(ThermoFisherScientific, Cat #A25603) according to the manufacturer'sinstructions. A PCR mix containing master mix, primers for progesteronereceptor (PR) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)endogenous control (ThermoFisherScientific, PR: Cat #Hs01556702_ml andGAPDH: 4326317E), RNase free water (ThermoFisherScientific, Cat #AM9938)was prepared and 8 μl of this mix was added to each well of a MicroAmpOptical 384-well plate. Cell lysates (2 μl) were then added to therespective wells and samples were analyzed using the QuantStudio6machine using the fast cycling conditions provided in the kit.Inhibition of PR induction was analyzed and IC50 values were calculatedusing the GraphPadPrism 6.0 software. In general, the activity in thisassay tracked similarly to the MCF-7 inhibition data shown in Table 1.Many of the compounds of the invention potently suppressed PR inductionwhen stimulated by 1 nM E2.

ER Degradation Assay in MCF-7 Cells

MCF-7 cells were stripped for 3 days in phenol red-free RPMI1640 mediacontaining 10% charcoal-stripped fetal bovine serum (CS-FBS) and 1%Penicillin/streptomycin (P/S). Cells were seeded in 6 well plates at adensity of 4×10{circumflex over ( )}5 cells/well (volume of 2 ml/well).On the following day, plates were treated with the test compounds (3×concentration in media, volume of 1 ml/well added). The cells wereincubated with test compounds for 48 h. Cells were washed and lysedusing 70 μl/well of CelLyticM (Sigma, Cat #C2978) lysis buffercontaining protease and phosphatase inhibitors at room temperature for15 minutes. The lysates were centrifuged at 15000 rpm for 15 mins andthe supernatant was collected and concentration were analyzed using theBicinchoninic acid assay (BCA). Proteins (25 μg) were loaded andseparated on a 4-15% polyacrylamide gel. Proteins were then transferredto a PVDF membrane and the membranes were then incubated with the ERαprimary antibody (Cell Signaling, Cat #13258; 1:1000) and the vinculinprimary antibody (Sigma, Cat #V9131, 1:1000). Membranes were incubatedwith the respective secondary antibodies, probed with chemiluminescentsubstrates (ThermoFisherScientific, Dura (ERα): Cat #34075 and Pico(Vinculin): Cat #34080), and images were captured using the AzureBiosystems c600 machine. Images were analyzed using the AzureSpotsoftware. Several tested compounds disclosed herein decreased expressionof the ER.

Immature Rat Uterine Assay

Sprague-Dawley rat pups were weaned at 19 days of age, randomized intogroups (n=6), and administered vehicle (aqueous 20% HPBCD, 10% PEG400 inH₂O), E2 (0.01 mg/kg), test compounds (0.1 mg/kg-3 mg/kg) in combinationwith E2 (0.01 mg/kg), either by subcutaneous injection or by oralgavage, once daily for three consecutive days. Twenty-four hours afterthe final dose, all animals were killed by carbon dioxide inhalation.Body weights and wet uterine weights were recorded for each animal.GraphPadPrism 6.0 software was used to analyze data. For example,compound D-102 suppressed wet uterine weight to baseline with an oraldose of 3 mg/kg.

MCF-7 Xenograft Models

Female athymic nude mice [Crl:NU(NCr)-Foxn1nu] are used for tumorxenograft studies. Three days before tumor cell implantation, estrogenpellets (0.36 mg E2, 60-day release; Innovative Research of America,Sarasota, Fla., USA) are implanted subcutaneously between the scapulaeof test animals with a sterilized trochar. MCF-7 human breastadenocarcinoma cells are cultured to midlog phase in RPMI-1640 mediumcontaining 10% fetal bovine serum, 100 U/ml penicillin G, 100 μg/mlstreptomycin sulfate, 2 mmol/l glutamine, 10 mmol/l HEPES, 0.075% sodiumbicarbonate, and 25 μg/ml gentamicin. On the day of tumor cellimplantation, the cells are trypsinized, pelleted, and resuspended inPBS at a concentration of 5×107 cells/ml. Each test mouse receives 1×10⁷MCF-7 cells implanted subcutaneously in the right flank, and tumorgrowth is monitored. Volume is calculated using the following formula:tumor volume (mm³)=l×w2/2, where w=width and l=length in mm of an MCF-7tumor. When necessary, tumor weight is estimated on the basis of theassumption that 1 mm³ of tumor volume is equivalent to 1 mg tumor wetweight. Fourteen days after tumor cell implantation (designated as day 1of the study), mice are 9 weeks of age, with body weights ranging from21.4 to 32.5 g, individual tumor volumes ranging from 75 to 144 mm³, anda group mean tumor volume (MTV) of 108 mm³. The mice are randomized intogroups of 9-15 animals each and treated with vehicle, control SERM suchas tamoxifen (1 mg/animal every other day), and test compound (0.3, 1,3, 10, 30, 60, 90, and 120 mg/kg daily). Tumor volumes are evaluatedtwice per week. The tumor endpoint is defined as an MTV of 1500 mm³ inthe control group. Animals are also monitored for partial regression(PR) and complete regression responses. Treatment tolerability isassessed by body weight measurements and frequent observation forclinical signs of treatment-related adverse effects. Animals with weightloss exceeding 30% for one measurement, or exceeding 25% for threemeasurements, are humanely sacrificed and their deaths are classified astreatment-related deaths. Acceptable toxicity is defined as a group meanbody weight loss of less than 20% during the study and not more than onetreatment-related death among 10 treated animals, or 10%. At the end ofthe study, the animals are sacrificed by terminal cardiac puncture underisoflurane anesthesia.

TABLE 1 MCF-7 Proliferation Inhibition Assay Compound IC₅₀ D-01 ++ D-02++ D-03 ++ D-08 ++ D-12 + D-13 ++ D-15 +++ D-16 +++ D-28 +++ D-29 +++D-32 +++ D-33 +++ D-34 +++ D-36 +++ D-37 +++ D-39 +++ D-40 +++ D-46 +++D-50 +++ D-52 +++ D-66 +++ D-67 +++ D-68 +++ D-69 +++ D-70 +++ D-78 +++D-85 +++ D-87 +++ D-88 +++ D-89 +++ D-90 +++ D-91 +++ D-96 +++  D-101+++  D-102 +++  D-103 +++  D-104 +++ LA-18 +++ LA-19 +++ LA-21 +++ LA-22+++ LA-31 +++ LA-32 +++ LA-33 +++ Bx-06 +++ Bx-07 +++ BT-05 +++ BT-12+++ BT-17 +++ +++ IC₅₀ < 1 nM; ++ IC₅₀ > 1 nM < 10 nM; + IC₅₀ > 10 nM;na = data not available

1. A compound according to formula I′

wherein: B is nitrogen or carbon; D is carbon; A is a fused ring systemselected from the group consisting of:

each R_(e) is independently selected from hydrogen, halogen, OH, O(CO)R,O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacent R_(e)together form:

R is C₁-C₆ alkyl or aryl; R₁ and R₂ are each independently hydrogen orC₁-C₆ alkyl; each R₃ is hydrogen, C₁-C₁₂ acyl; C₁-C₁₂ acyloxy; each R₄is independently hydrogen, C₁-C₃ alkyl, fluorine or chlorine; each R_(h)is independently selected from hydrogen or CH₃; R_(g) is hydrogen, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, CN, fluorine, chlorine or bromine; each R_(a)is independently selected from: H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,phenyl (optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

X is O, S, CH₂, NH or a bond when B is carbon, or CH₂ or a bond when Bis nitrogen; Y and Z are each independently selected from CR_(f) or N; Uand V are each independently selected from CR_(a) or N; each R_(f) isindependently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine or chlorine; and Wis —CHR′—CHR′—NH—C₁-C₄alkyl, —CHR′—CHR′—NH—C₁-C₄fluoroalkyl,—CHR′—CHR′—NH—C₃-C₆cycloalkyl, —CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein W is—CH₂—CH₂—NH—CH₂—CH₂—CH₃; —CH₂—CH₂—NH—CH₂—CH₂—CH₂F;

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein A is:


4. The compound of claim 1, wherein Y and Z are each CR_(f) and U and Vare each CR_(a).
 5. The compound of claim 1, having a structureaccording to formula II′

wherein: each R_(a) is independently selected from H, C₁-C₃ alkyl,phenyl (optionally substituted with 1-3 groups selected from fluorine,chlorine, C₁-C₃ alkyl, CN, OC₁-C₃ alkyl, OH), OH, OC₁₋₃alkyl, CN,fluorine, chlorine, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or twoadjacent R_(a) together form:

R is C₁-C₆ alkyl or aryl; R₁ and R₂ are each independently hydrogen orC₁-C₆ alkyl; each R₃ is independently hydrogen; C₁-C₁₂ acyl or C₁-C₁₂acyloxy; each R₄ is independently hydrogen, C₁-C₃ alkyl, fluorine orchlorine; each R_(e) is independently selected from hydrogen, halogen,OH, O(CO)R, O(CO)NR₁R₂, OPO₃, OSO₃, O(SO₂)NR₁R₂, or wherein two adjacentR_(e) together form:

each R_(f) is independently H, C₁-C₃ alkyl, OC₁-C₃ alkyl, fluorine orchlorine; R_(g) is hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, CN,fluorine, chlorine or bromine; X is CH₂ or a bond; Z is selected fromCR_(f) or N, and Y is N; U and V are each independently selected fromCR_(a) or N; and W is —CHR′—CHR′—NH—C₁-C₄alkyl,—CHR′—CHR′—NH—C₁-C₄fluoroalkyl, —CHR′—CHR′—NH—C₃-C₆cycloalkyl,—CHR′—CHR′—NH—C₁-C₄alkyl-C₃-C₆cycloalkyl,

wherein each R′ is independently H or C₁-C₃alkyl; or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 5, wherein: X is CH₂;Y is N; Z is CR_(f); U and V are each CR_(a); R_(g) is F, C₁ or CH₃;each R_(a) is independently selected from H, OH, CH₃ and C₁; each R_(f)is H; and W is —CH₂—CH₂—NH—CH₂—CH₂—CH₃, —CH₂—CH₂—NH—CH₂—CH₂—CH₂F,

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim6, wherein each R_(e) is independently selected from hydrogen or OH, orwherein two adjacent R_(e) together form:

and wherein R₃ is H and R₄ is H. 8-19. (canceled)
 20. The compound ofclaim 1, having a structure according to formula VII′:

wherein: Q is H or F; R_(a) is CH₃, Cl or OMe; and Ra′ is H, F or OH; ora pharmaceutically acceptable salt thereof.
 21. The compound of claim20, wherein R_(a) is CH₃ and R_(a)′ is H.
 22. The compound of claim 1,having a structure according to formula VIII′:

wherein: Q is H or F; R_(a) is CH₃, Cl or OMe; and R_(a)′ is H, F or OH;or a pharmaceutically acceptable salt thereof.


25. The compound of claim 24, wherein R_(a) is CH₃ and R_(a)′ is H. 26.The compound of claim 1, having a structure according to formula X′:

wherein: Q is H or F; R_(a) is CH₃, Cl or OMe; and R_(a)′ is H, F or OH;or a pharmaceutically acceptable salt thereof.
 27. The compound of claim26, wherein R_(a) is CH₃ and R_(a)′ is H.
 28. A compound according toclaim 1, wherein the compound is selected from:(5R,6S)-5-(4-(2-(Ethylamino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-(Ethylamino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol;(5R,6S)-5-(4-(2-((cyclopropylmethyl)amino)ethyl)phenyl)-6-(o-tolyl)-5,6,7,8-tetrahydronaphthalen-2-ol;5-(4-(2-(Ethylamino)ethyl)phenyl)-6-(4-isopropylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;6-(4-Isopropylphenyl)-5-(4-(2-(propylamino)ethyl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;5-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenyl)-6-(4-isopropylphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol;3-(4-(2-(Cyclopropylamino)ethyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol;3-(4-(2-((Cyclopropylmethyl)amino)ethyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol;3-(4-((1-Propylazetidin-3-ylidene)methyl)phenoxy)-2-(o-tolyl)benzo[b]thiophen-6-ol;5-(4-(2-(Cyclopropylamino)ethyl)benzyl)-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-8-ol;and5-(4-(2-(Ethylamino)ethyl)benzyl)-4-(o-tolyl)-2,3-dihydrobenzo[b]oxepin-8-ol.29. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 30. A method of treating adisease, syndrome, illness, or symptom associated with insufficient oroverabundant estrogen levels in a mammal in need thereof, comprisingadministering to said mammal an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof.
 31. A method oftreating a cancer selected from the group consisting of prostate cancer,breast cancer, endometrial cancer, lung cancer, hepatocellular cancer,lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer,thyroid cancer, testicular cancer, leukemia, and ovarian cancer in amammal in need thereof, comprising administering to said mammal aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.